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EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING 10 - 13 October 2022 Singapore Organisers Prof Vinay Tergaonkar Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore Prof Eric Gilson Institute for Research on Cancer and Aging, France About The Workshop DNA damage and inflammation are two major contributing factors of aging that are intimately connected. Indeed, recent ground-breaking studies revealed how DDR can mobilize the immune system by inducing the expression of pro-inflammatory factors as well as ligands for immune receptors. The activation of immune response is induced by different DDR components including DNA damage sensors, transducer kinases, and effectors. For instance, the release of DNA fragments in the cytosol activates the cGAS-STING pathway, the expression of interferon genes and the inflammatory response. Conversely, chronic inflammation has recently emerged as an important mutagenic and cancer promoting process by generating reactive oxygen and nitrogen reactive species. These discoveries have profound implications not only in aging mechanisms but also in cancer therapy and in strategies to prevent age-related diseases. Thus, linking DNA damage response and immunity in the aging process is a novel concept with rapid intellectual advances that deserve intensive interaction between researchers of different fields. To ensure in-depth coverage of all topics relating to DNA damage, immunity and aging, the following thematic scientific sessions are planned: · Session 1: DNA damage and aging · Session 2: Inflammation, immunity and aging · Session 3: Generation and signaling of cytosolic DNA · Session 4: Cancer immunity This EMBO Workshop on this topic represents the ideal environment to fuel intellectual exchange and build-up of long-term, extensive synergies amongst immunologists and researchers on DNA damage response and aging. Table Of Contents Program Schedule P 7 - P 10 Session 1: P 13 - P 16 Immunity & Aging I Session 2: P 19 - P 24 Immunity & Aging II Session 3: P 27 - P 30 DNA Damage & Aging I Session 4: P 33 - P 38 DNA Damage & Aging II Session 5: P 41 - P 44 DNA Damage & Aging III Session 6: P 47 - P 52 Cancer I Session 7: P 55 - P 56 Cancer II Session 8: P 59 - P 60 Cancer III Abstract Submissons P 63 - P 72 Short Oral Presentations Abstract Submissons P 75 - P 110 Poster Presentations Notes P 111 - P 120 Acknowledgements P 121 - 128 PROGRAM SCHEDULE Program Schedule (Day 1 - 2) Day 1 - 10 October 2022, Monday 8.30am Registration / Arrival of guests (Coffee | Mixer) 9.00am Welcome Remarks: Vinay Tergaonkar 9.10am Opening Address: Barry Halliwell Chairman, BMRC Advisory Council, A*STAR, Singapore Senior Advisor, Office of the Senior Deputy President and Provost, NUS, Singapore Distinguished Professor, Yong Loo Lin School of Medicine, NUS, Singapore SESSION 1: Chaired by: Ashok Venkitaraman Immunity & Aging I Cancer Science Institute, Singapore 9.20am Fabrizio d’Adda di Fagagna The FITC Institute of Molecular Oncology, Milan, Italy Keynote: Telomere Biology in Aging and Disease 10.10am Jan Rehwinkel University of Oxford, UK Viral Targeting Of The cGAS Pathway 10.40am COFFEE BREAK 11.10am Nicolas Manel Curie Institute, Paris, France Nuclear Envelope Disruption Triggers Hallmarks Of Aging In Lung Alveolar Macrophages 11.40am Vinay Tergaonkar Institute of Molecular and Cell Biology, Singapore Molecular Determinants Of Telomere Mediated Inflammation 12.10pm LUNCH SESSION 2: Chaired by: Vincent Géli Immunity & Aging II Marseille Cancer Research Centre, Marseille, France 1.25pm Florent Ginhoux Institut Gustave Roussy, Villejuif, France Understanding Macrophage Heterogeneity 1.55pm Bing Su Shanghai Institute of Immunology, Shanghai, China Sin1 Mediated mTOR Signal In Lymphocyte Growth And Metabolism 2.25pm Violeta Serra Vall d’Hebron Institute of Oncology, Barcelona, Spain Advances Using Functional HRD To Identify PARP Inhibitor Sensitive Tumours 2.55pm Nadine Laguette Institut Genetique Humaine, Montpellier, France STING Is A Central Rheostat of Metabolic And Inflammatory Homeostasis 3.25pm COFFEE BREAK 3.55pm Microglial Dysfunction in Ataxia-Telangiectasia: Role Of The Cystolic DNA Sensing cGAS-STING Pathway Emily Talbot 4.05pm Determining The Molecular Mechanism Of Cellular Aging In The Premature Aging Syndrome Hutchinson-Gilford Progeria Mattheus Foo 4.15pm Toshio Suda Cancer Science Institute of Singapore, Singapore Self-Renewal And Expansion Of Hematopoietic Stem Cells Under The Stress 4.45pm DNA Damage, Lipids Mediators and Aging Aditi Uday, Gurkar 5.55pm Eric Gilson Institute for Research on Cancer and Aging, Nice, France The Role Of The Shelterin TRF2 Subunit In Cellular Aging: From Dividing To Post- Mitotic Cells P7 EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING 5.25pm MIXER / DISCUSSION (Meeting rooms #1-06, #2-08) End of Day 1 6:00pm Depart for dinner Day 2 - 11 October 2022, Tuesday 9.15am POSTERS (Coffee served) SESSION 3: Chaired by: John Sedivy DNA Damage & Aging I Brown University, Providence, USA 10.00am Marco Foiani IFOM, Milan, Italy Keynote: An Integrated Mechano-Response Mediated By ATR And ATM 10.50am cGAS Accelerates Mitotic Cell Death Through The NLRP3 Inflammasome Enaam Alghamdi 11.00am COFFEE BREAK 11.30am Ming Lei Institute for Precision Medicine, Jiaotong University, Shanghai, China A Novel Primate-Specific X-Linked Amplicon Maintains Spermatogonia Self-Renewal And Genome 12.00pm New Anti-Aging Targets In Progeria Identified Through Synthetic Rescue Genome Wide Arrayed CRISPR Screening Delphine Larrieu 12.10pm Ganglioside Based Immune Checkpoint Controls Senescent Cell Fate: A Paradigm Shift In Cancer & Aging? Julien Cherfils-Vicini 12.20pm Brian Kennedy National University of Singapore, Singapore Pillars And Hallmarks Of Aging From The Perspective Of Longevity Interventions 12.50pm LUNCH / POSTER SESSION 1 [01 - 16] SESSION 4: Chaired by: Eric Gilson DNA Damage & Aging II Institute for research on Cancer and Aging, Nice, France 2.35pm Jing Ye Personalized Aging Medicine Center, Ruijin Hospital, Jiaotong University, Shanghai, China The Evolutionary Trajectory Of Telomeric Protective Proteins In Zebrafish 3.05pm Sophie Postel-Vinay Institut Gustave Roussy, Villejuif, France Harnessing Genetic Vulnerabilities In Immuno-oncology: Novel Therapeutic Opportunities 3.35pm COFFEE BREAK 4.05pm James Chen Howard Hughes Medical Institute, University of Texas Southwestern Medical Center Dallas, USA Keynote: Igniting An Immune Response To DNA With cGAS 4.55pm Hyeseong Cho Ajou University of Medicine, Suwon, South Korea DNA Damage Response And Mitochondrial Dynamics 5.25pm Eiji Hara Osaka University, Osaka, Japan Cellular Senescence And Cancer: Relevance To Microorganisms End of Day 2 6.00pm Depart for Dinner P8 PROGRAM SCHEDULE Program Schedule (Day 3 - 4) Day 3 - 12 October 2022, Wednesday 9.15am POSTERS (Coffee served) SESSION 5: Chaired by: Hyunsook Lee DNA Damage & Aging III Seoul National University, Seoul, South Korea 10.00am Judith Campisi Buck Institute, Novato, USA Keynote: TBD 10.50am Nuclear Translocation Of Protein Arginine Methyltransferase 5 (PRMT5) Regulates The Immune Response To Replication Stress Anand D Jeyasekharan 11.00am COFFEE BREAK 11.30am Joao Passos Mayo Clinic, Rochester, USA Targeting Senescence For Healthier Aging: All Roads Lead To Mitochondria 12.00pm George Garinis IMBB-FORTH, Heraklion, Greece DNA Damage And Innate Immune Responses In Health And Disease 12.30pm LUNCH / POSTER SESSION 2 [17 - 32] SESSION 6: Chaired by: Fabrizio d’Adda di Fagagna Cancer I The FIRC Institute of Molecular Oncology & IGM-CNR (National Research Council), Milan, Italy 2.00pm Vincent Géli Marseille Cancer Research Centre, Marseille, France Telomerase Preserves Lung Function In Old Mice By Promoting Endothelial Cell Renewal And Preventing Cellular Senescence 2.30pm Hyunsook Lee Seoul National University, Seoul, South Korea Dynamic Interaction Of BRCA2 With The Telomeric G-Quadruplexes 3.00pm Karen Crasta National University of Singapore, Singapore Small Extracellular Vesicles From Therapy-Induced Senescent Breast Cancer Cells Elicit Paracrine Anti-Tumour Effects 3.30pm COFFEE BREAK 4.10pm Sunny Songyang Zhou Sun Yat-sen University Guangzhou Key Laboratory of Healthy Aging Research, Guangzhou, China Identification Of Key Regulators Of DNA Repair In Human Cells By Inducible CRISPR/ Cas9 Screens 4.40pm ATR Inhibition As A Therapeutic Strategy To Boost Antitumour Immune Reponses In Triple Negative Breast Cancer Giulia Bastianello 4.50pm ZNF524 Directly Interacts With Telomeric DNA And Supports Telomere Integrity Dennis Kappei 5.00pm Andrea Ablasser EPFL, Lausanne, Switzerland Keynote: The cGAS-STING Pathway In Aging-Associated Neurodegeneration End of Day 3 6:00pm Free and Easy Dinner P9 EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING Day 4 - 13 October 2022, Thursday 9.15am POSTERS (Coffee served) SESSION 7: Chaired by: Jan Karlseder Salk Institute, La Jolla, USA Cancer II 10.00am John Sedivy Brown University, Providence, USA Keynote: Involvement of Retrotransposons in Aging and Age-Related Diseases 10.50am The Relationship Between Spliceosome Mutations And Immune Activation In Cancer Katrina Lappin 11.00am COFFEE BREAK 11.30am Ashok Venkitaraman Cancer Science Institute, Singapore Regulation Of DNA Recombination By The BRCA2 Cancer Suppressor And Its Modulation By Drug-Like Small Molecules 12.00pm Cisplatin-Induced DNA Damage Triggers MRE11a Proteasomal Degradation Mediated By UBQLN4 In Solid Tumours Dave Hoon 12.10pm Potassium Efflux By Nigericin Triggers ZAKa-Driven Ribotoxic Stress And NLRP1 Inflammasome Activation Pritisha Rozario 12.20pm LUNCH / POSTER SESSION 3 [33 - 46] SESSION 8: Chaired by: Violeta Serra Cancer III Vall d’Hebron Institute of Oncology, Barcelona, Spain 1.50pm Cdkn1a-Driven Expression Of Telomerase Improves Insulin-Resistance By Preventing Obesity Associated Senescence Phenotype In Adipose Tissue Laura Braud 2.00pm Chris Lord The Institute of Cancer Research, London, UK Using Forward And Reverse Translation Approaches To Understand DDR Inhibitor Response 2.30pm Jan Karlseder Salk Institute, La Jolla, USA Closing Keynote: Telomere To Mitochondria Signaling Prevents Cancer Initiation 3.20pm Thank You Note Hong Wanjin Institute of Molecular and Cell Biology, A*STAR, Singapore 3.30pm Closing Remarks Eric Gilson End of Workshop P 10 Session 1 Immunity & Aging I Chaired by: Ashok Venkitaraman SESSION 1: IMMUNITY & AGING I SPEAKERS Dr. Fabrizio d’Adda di Fagagna PRINCIPAL INVESTIGATOR (PI) IFOM & IGM-CNR Dr Fabrizio is a molecular and cell biologist with twenty years of experience as a group leader. He has devoted his professional life to understanding the critical biological mechanisms underlying aging and cancer. Dr Fabrizio works at IFOM (Milan) and IGM-CNR (Pavia) in Italy. Together with his group, they study the connection between DNA damage and disease. Dr Fabrizio is generally recognized for his discoveries in telomere biology and cellular senescence. He has been awarded the European Research Council (ERC) advanced grant twice and is a member of the European Molecular Biology Organization (EMBO). Recently, his group has recently identified what they believe is the main cause of several diseases of aging: loss of integrity of the telomeres, the protective caps at the ends of our chromosomes. Following that discovery, they have developed a universal inhibitor of cellular aging based on RNA therapeutics and have validated it in several in vivo models of human diseases. Telomere Biology In Aging And Disease During aging, senescent cells accumulate in tissues and organs, which become unable to proliferate and function properly. Telomeric shortening and damage trigger most, if not all, the downstream pathways leading to senescence and disease. The DNA damage response (DDR) pathways activated by short or damaged telomeres are necessary for cellular senescence enforcement. We have shown that damage-induced long non-coding RNAs (dilncRNAs) are generated at sites of DNA damage, including telomeres. Antisense oligonucleotides (ASOs) against such RNAs allow site-specific DDR inhibition (Francia et al. Nature 2012, Michelini et al. Nature Cell Biology 2017, Pessina et al. 2019). Telomeric ASOs inhibit DDR activation at dysfunctional telomeres in cultured cells and in vivo in mice (Rossiello et al. Nature Communications 2017). In a mouse model of Hutchinson-Gilford Progeria Syndrome (HGPS), selective DDR inhibition at telomeres improve tissue homeostasis, reduce inflammation and extend lifespan (Aguado et al. Nature Communications 2019). Lung fibrosis and altered hematopoiesis are human conditions associated with short telomeres and telomerase mutations. Telomerase knockout mice recapitulate these pathologies. In this model, tASO improves respiratory and hematopoietic systems. In addition, we recently observed that telomeric shortening or dysfunction cause an increase in the levels of ACE2, the SARS-CoV-2 receptor, in humans and in mice and that selective tDDR inhibition prevents it in vivo. P 13 EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING Prof. Jan Rehwinkel GROUP LEADER, MRC HUMAN IMMUNOLOGY UNIT MRC Weatherall Institute of Molecular Medicine, University of Oxford, UK Jan is interested in the molecular mechanisms underlying host-pathogen interactions, especially how cells detect virus infection. His work lies at the intersection of immunology, virology and molecular biology. After his undergrad at the University of Heidelberg, Jan joined the European Molecular Biology Laboratory (EMBL) as a PhD student. Under supervision of Elisa Izaurralde, Jan studied post-transcriptional control of messenger RNA, and obtained a PhD in 2007. This background in RNA biology led him to develop an interest in nucleic acids in innate immunity. As a postdoctoral fellow, he joined the group of Caetano Reis e Sousa, then at the Cancer Research UK London Research Institute (London, UK). Jan investigated how RNA viruses are recognised by innate immune sensors. In 2012, Jan moved to the University of Oxford, UK. His laboratory is part of the MRC Human Immunology Unit and the MRC Weatherall Institute of Molecular Medicine. Jan’s research dissects nucleic acid sensing by innate receptors in the context of virus infection, autoinflammatory disease and cancer. Viral Targeting Of The cGAS Pathway Nucleic acid sensing is a fundamental process in the immune system. Viruses introduce DNA or RNA genomes into cells, which often serve as molecular signatures of infection, detected by nucleic acid sensors. cGAS is a sensor for double-stranded DNA which detects many viral pathogens and ‘self’ DNA, thereby driving sterile inflammation. cGAS produces cGAMP, activating STING, which signals for innate immune activation. Viruses antagonize the cGAS pathway to dampen innate immunity and facilitate their replication. We found that the cGAS pathway was required for type I interferon (T1-IFN) induction during Varicella-Zoster virus (VZV) infection. Viral gene overexpression screening identified the VZV tegument protein ORF9 as a cGAS antagonist. Ectopically and virally expressed ORF9 bound to cGAS and reduced the T1-IFN response to transfected DNA. ORF9 and cGAS also interacted directly in a cell-free system and phase- separated together with DNA. Taken together, we uncovered the importance of the cGAS pathway for VZV recognition and identified a viral cGAS antagonist. cGAMP not only activates STING but also transfers to other cells. We report that infection with multiple viruses depleted cGAMP channels from cells. This included HSV-1 that targeted the VRAC subunits LRRC8A/C, SLC46A2, and P2X7R for degradation. The HSV-1 protein UL56 was required and sufficient for these effects. We propose this limits innate immunity by reducing cell-to-cell communication via cGAMP. P 14 SESSION 1: IMMUNITY & AGING I SPEAKERS Prof. Nicolas Manel RESEARCH DIRECTOR Institut Curie Nicolas Manel received his PhD from University of Montpellier, France in 2005. He then received training as a postdoctoral fellow in the lab of Dan Littman at NYU. In 2010, he became an INSERM principal investigator at Institut Curie in Paris, France. The Manel lab focuses on understanding how cells discriminate self from non-self or altered self. The lab pioneered the study of the cGAS-STING pathway in the context of HIV infection. The lab currently studies the regulation of innate sensors in response to viruses and self, their evolution during aging, and their use in immuno-oncology. Nuclear Envelope Disruption Triggers Hallmarks Of Aging In Lung Alveolar Macrophages Aging is characterized by gradual immune dysfunction and increased risk for many diseases, including respiratory infections. Genomic instability is thought to play a central role in the aging process but the mechanisms that damage nuclear DNA in aging are insufficiently defined. Cells that migrate or reside within confined environments experience forces applied to their nucleus, leading to transient nuclear envelope (NE) ruptures. NE ruptures are associated with DNA damage, and Lamin A/C is required to limit these events. Here, we show that Lamin A/C protects lung alveolar macrophages from NE rupture and hallmarks of aging. Lamin A/C ablation in immune cells results in a selective depletion of lung alveolar macrophages (AM) and a heightened susceptibility to influenza infection. Lamin A/C-deficient AM that persist display constitutive nuclear envelope rupture marks, DNA damage and p53-dependent senescence. In wild-type mice, we found that AM migrates within constricted spaces in vivo, at heights that induce NE rupture and DNA damage. AM from aged wild-type mice and from Lamin A/C-deficient mice share an upregulated lysosomal signature with CD63 expression, and we find that CD63 is required to clear damaged DNA in macrophages. We propose that induction of genomic instability by NE disruption represents a mechanism of aging in alveolar macrophages. P 15 EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING Prof. Vinay Tergaonkar RESEARCH DIRECTOR Institute of Molecular and Cell Biology, A*STAR Vinay Tergaonkar obtained his Ph.D. (2001) from NCBS Bangalore, through an international cancer society (UICC) fellowship for collaborative research at Tufts University, Boston, USA. He has been a fellow (2001-2004) and a special fellow (2004-present) of the Leukemia and Lymphoma Society of America and conducted his postdoctoral studies at the Salk Institute for Biological Studies, La Jolla, California. He currently serves as Research Director at Institute for Molecular and Cell Biology (IMCB), Singapore, and a Professor at School of Medicine at National University of Singapore. He serves on Editorial Boards of 1) Science Advances (AAAS), 2) Molecular and Cellular Biology (American Society for Molecular Biology), 3) Biochemical Journal (Portland Press). Work from his lab has received international recognition including the British council development award (2014), the Premiers’ fellowship from Government of South Australia (2015) and University of Macau Distinguished Professorship (2019). Molecular Determinants Of Telomere Mediated Inflammation Over 90% of human cancers attain immortality by transcriptional reactivation of an enzyme called telomerase reverse transcriptase (TERT). How and why TERT is reactivated in the vast majority of human cancers remain as fundamental unsolved problems in biology. I will present unpublished and unexpected set of results which suggest why TERT is reactivated in human cancers. P 16 Session 2 Immunity & Aging II Chaired by: Vincent Géli SESSION 2: IMMUNITY & AGING II SPEAKERS Prof. Florent Ginhoux LABORATORY DIRECTOR Gustave Roussy Senior PI & SIgN A*STAR Florent Ginhoux graduated in Biochemistry from the University Pierre et Marie CURIE (UPMC), Paris VI, obtained a Masters degree in Immunology from the Pasteur Institute in 2000 and his PhD in 2004 from UPMC, Paris VI. As a postdoctoral fellow, he joined the Laboratory of Miriam Merad in the Mount Sinai School of Medicine (MSSM), New York, where he studied the ontogeny and the homeostasis of cutaneous dendritic cell populations, with a strong focus on Langerhans cells and Microglia. In 2008, he became an Assistant Professor in the Department of Gene and Cell Medicine, MSSM and member of the Immunology Institute of MSSM. He joined the Singapore Immunology Network (SIgN), A*STAR in May 2009 as a Junior Principal Investigator and became Senior Principal Investigator in 2014. He joined the EMBO Young Investigator (YIP) program in 2013 and is a Web of Science Highly Cited Researcher since 2016. He is also an Adjunct Visiting Associate Professor in the Shanghai Immunology Institute, Jiao Tong University, in Shanghai, China since 2015 and Adjunct Associate Professor in the Translational Immunology Institute, SingHealth and Duke NUS, Singapore since 2016. He is now a Laboratory Director in Gustave Roussy focusing on pediatric cancers and the role of myeloid cells in tumor progression and became an EMBO member in 2022. Understanding Macrophage Heterogeneity Resident tissue macrophages (RTMs) have a broad spectrum of immune- and non-immune-related tissue-supporting activities. The roots of this heterogeneity and versatility are only beginning to be understood. Here, we propose a conceptual framework for considering the RTM heterogeneity that organizes the factors shaping RTM identity within four cardinal points: (1) ontogeny and the view that adult RTM populations comprise a defined mixture of cells that arise from either embryonic precursors or adult monocytes; (2) local factors unique to the niche of residence, evolving during development and aging; (3) inflammation status; and (4) the cumulative effect of time spent in a specific tissue that contributes to the resilient adaptation of macrophages to their dynamic environment. P 19 EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING Prof. Bing Su DIRECTOR; CHAIR Shanghai Institute of Immunology; Shanghai JiaoTong University School of Medicine Dr. Bing Su is the Director of Shanghai Institute of Immunology and Chair of Department of Immunology and Microbiology at Shanghai JiaoTong University School of Medicine, Co-Founding Director of Shanghai JiaoTong University School of Medicine-Yale University Institute for Immune Metabolism (SYIIM) and an Adjunct Professor at Department of Immunobiology at Yale University School of Medicine. Dr. Su also holds a KC Wong Chair Professorship at Shanghai JiaoTong University. Dr. Su’s research focuses on the intracellular signal transduction pathways controlled by the mammalian target of rapamycin (mTOR) and the mitogen activated protein kinases (MAPKs). He studies the roles of these intracellular signaling cascades in immune regulation and vascular function. Dr. Su has published over 110 peer-reviewed papers, many of which were in high-impact journals such as Nature, Cell, Nature Genetics, Nature Immunology, Immunity, Molecular Cell, EMBO J, etc. Sin1 Mediated mTOR Signal In Lymphocyte Growth And Metabolism The mammalian target of rapamycin (mTOR) is an evolutionarily conserved protein kinase with a central role in cell growth and metabolism. Multiple mTOR-containing protein complexes (mTORCs) exist to mediate mTOR function via controlling many cellular targets including the members of the protein kinase (PK)A/PKG/PKC (AGC) family. Sin1 is an essential component of mTORC2 with crucial roles in regulating immune cell growth and metabolism. The function of Sin1-mTORC2 has been explored in immune cell growth and metabolism but its roles in tumor growth and anti-tumor immunity is still largely unclear. We will present data on Sin1-mTORC2’s roles in these processes. P 20 SESSION 2: IMMUNITY & AGING II SPEAKERS Dr. Violeta Serra GROUP LEADER Vall d’Hebron Institute of Oncology After completing her PhD in the field of cellular aging and telomeres from Newcastle University, in the UK, in 2001, Dr Violeta studied cancer chemoresistance with a Marie Curie Postdoctoral Fellowship at the Charité (Berlin). In 2006, she joined the Vall d’Hebron Institute of Oncology (VHIO, Barcelona) to explore the mode of action and mechanisms of resistance to PI3K-pathway and CDK4/6 inhibitors. Since 2014, Dr Violeta has led the Experimental Therapeutics Group, where she expanded her research into the mode of action of targeted therapies for tumors harboring DNA damage repair deficiencies, such as those from germline BRCA1/2-mutation carriers. Overall, her research is focused on the development of predictive and biomarkers for targeted agents in breast cancer. She have been awarded with grants from the Spanish Ministry of Health, the Susan G. Komen and the Breast Cancer Now Foundations. Dr Violeta is a member of the AACR, and serves on the Editorial Board of Clinical Cancer Research. Advances Using Functional HRD To Identify PARP Inhibitor Sensitive Tumours Tumors with defective DNA repair by the homologous recombination repair (HRR) pathway are exquisitely sensitive to DNA damaging agents and to novel agents that block parallel pathways, including PARP inhibitors (PARPi). PARPi has been approved for the treatment of ovarian, breast, prostate and pancreatic cancers. Currently used selection biomarkers to enrich the population of patients most likely to respond, namely the platinum-sensitive or HRR-gene mutated patients, have limited predictive capacity. There is a need for more specific biomarkers to guide personalized treatment. Genomic scar signatures have been proposed as a putative biomarker associated with DNA repair deficiency. A major limitation of these assays is the lack of specificity in HRR-altered tumors once they have restored the HRR function as a mechanism of drug resistance. Instead, RAD51 foci formation is a functional and dynamic biomarker of HRR that correlates with PARPi response. We will review the current knowledge on PARPi sensitivity and resistance in these cancers, the potential of therapeutic combinations and our advances using functional HRD to identify PARPi sensitive tumors. P 21 EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING Dr. Nadine Laguette RESEARCH DIRECTOR The French National Centre for Scientific Research (CNRS) Nadine Laguette is a research director at the CNRS and heads the “molecular bases of inflammation” laboratory in Montpellier (France) that takes interest in uncovering the molecular mechanisms underlying pathological inflammation. She studied molecular biology and genetics at the Royal Holloway college of the University of London (UK). During her PhD in cell biology at the University of Paris V (France) she studied HIV biology. She joined the institute of human genetics as a postdoctoral fellow to work on virus-host interactions where she secured a research scientist position before establishing her own research group. She is the recipient of prestigious awards (Sidaction, Sanofi-pasteur institute, CNRS Bronze medal etc.) and grants (ERC starting grant, ERC Proof of concept etc.). STING Is A Central Rheostat of Metabolic And Inflammatory Homeostasis Concerted alteration of immune and metabolic homeostasis underlies several inflammation-related pathologies, ranging from metabolic syndrome to cancer. We recently explored the coordination of nucleic acid-dependent inflammatory responses and metabolic homeostasis. We reveal that the Stimulator of Interferon Genes (STING) protein regulates metabolic homeostasis through inhibition of the Fatty acid desaturase 2 (FADS2), a rate-limiting enzyme in polyunsaturated fatty acids (PUFAs) desaturation. STING ablation and agonist-mediated degradation increased FADS2 activity and led to accumulation of PUFAs that drive thermogenesis. PUFAs in-turn inhibited STING, thereby regulating antiviral responses and contributing to resolve STING-associated inflammation. Thus, we have unveiled a negative regulatory feedback loop between STING and FADS2 that fine-tunes inflammatory responses. Our results highlight the role of metabolic alterations in human pathologies associated with aberrant STING activation and STING targeting therapies. Such implications will be discussed, notably for chronic inflammatory pathologies and tumorigenesis. P 22 SESSION 2: IMMUNITY & AGING II SPEAKERS Prof. Toshio Suda SENIOR PRINCIPAL INVESTIGATOR Cancer Science Institute of Singapore, National University of Singapore Toshio Suda studies hematopoietic stem cells (HSCs) and HSC niches. Although stem cells differentiate along with a cell autonomous intrinsic program, this process is influenced by the microenvironment of the stem cells niche. His past work encompasses the purification of HSCs, identification of cytokine signaling in hematopoiesis, and the characterization of HSC niches in bone marrow (BM). He identified the endosteal niche for HSC niche, and subsequently established the new field of oxidative stress and stem cell aging. Dr. Suda has shown that niche cells regulate stem cells through direct adhesion and through the secretion of humoral niche factors such as cytokines, chemokines and extracellular matrix molecules. Together, these niche components and stem cells are thought to form a functioning unit to maintain tissue homeostasis. Self-Renewal And Expansion Of Hematopoietic Stem Cells Under The Stress Stem cells are defined as cells having a self-renewal activity and multi-differentiation capacity. Both are tightly controlled to maintain hematopoietic stem cell (HSC) homeostasis in the adult bone marrow. Expansion technology of HSCs has recently shown significant progress and it is promising for the transplantation after severe chemotherapy in cancer patients. During fetal development, both HSC expansion (self-renewal) and differentiated hematopoietic cell production (differentiation) are required to sustain the hematopoietic system for body growth. However, it remains unclear how these two seemingly opposite tasks are accomplished within the short embryonic period. Here, we used in vivo genetic tracing to analyze the formation of HSCs and progenitors from intra-arterial hematopoietic clusters, which contain HSC precursors and express the Hlf transcription factor. Through kinetic study, we find the simultaneous formation of HSCs and defined progenitors—previously regarded as HSC descendants—from the Hlf-positive precursor population, followed by prompt hierarchical hematopoietic structure formation in the fetal liver in a HSC-independent manner. The transcription factor Evi1 is heterogeneously expressed within the precursor population, with Evi1hi cells predominantly localized to intraembryonic arteries and preferentially giving rise to HSCs. By genetically manipulating Evi1 expression, we can alter HSC and progenitor output from precursors in vivo. These data suggest that HSCs minimally contribute to the generation of progenitors and functional blood cells. On the basis of these findings, we are now investigating how to protect the HSC genome from the DNA damage in vitro culture by focusing on the function of thrombopoietin. P 23 EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING Prof. Eric Gilson DIRECTOR OF IRCAN University Côte d’Azur, Nice, France Eric Gilson is renowned for his pioneering work on telomere chromatin and links with cancer and aging. Beyond his own research, his broader questions about aging biology led him to found IRCAN in 2012. Continuing this approach, he is coordinating, under the umbrella of Inserm, national (AGEMED) and international (InterAging) networks on aging biology. Eric Gilson also heads up a Sino-French laboratory on Aging in partnership with the Personalized Aging Medicine Center (APMC) at Ruijin Hospital in Shanghai, affiliated with Jiaotong University. The Role Of The Shelterin TRF2 Subunit In Cellular Aging: From Dividing To Post-Mitotic Cells A well-established driver of mitotic cell aging is cell division-mediated telomere erosion, a process that does not occur in post-mitotic cells such as neurons. Much less is not known on the role of telomeres in the aging process of post-mitotic cells. We recently showed that in myofiber aging the expression of Telomeric repeat-binding factor 2 (TRF2: pivotal component of the telomere-capping Shelterin complex) decreases but without inducing telomere damage and senescence. Instead, this TRF2 downregulation leads to SIRT3 downregulation, ROS accumulation, mitochondrial dysfunction and FOXO3A translocation into the nucleus. The FOXO3A relocates to telomeres, where it acts as protective factors to compensate for the telomere-uncapping effect of TRF2 diminution. As a second approach, we assessed TRF2 expression and levels in the murine hippocampus during aging, showing that TRF2 decreases over time. Knocking down TRF2 in murine hippocampus leads to an impaired cognitive phenotype affecting episodic and contextual memory. Furthermore, we assessed whether inhibiting the DDR could rescue the observed cognitive phenotype and indeed, we could show a rescue of the cognitive deficit upon ATM inhibition. Finally, we assessed the effect of TRF2 overexpression in old mice and showed that it rescues episodic and contextual memory while further impairing spatial memory. Therefore, in two types of post-mitotic cells, skeletal myofiber and neuron, there is an age- dependent TRF2 decline that contributes to their aging process. P 24 Session 3 DNA Damage & Aging I Chaired by: John Sedivy SESSION 3: DNA DAMAGE & AGING I SPEAKERS Prof. Marco Foiani PRINCIPAL INVESTIGATOR AND FULL PROFESSOR IFOM ETS & University of Milan Marco Foiani studied at the University of Milan and moved to NIH-USA (1989-91) in the laboratory of dr. Alan Hinnebush for his postdoctoral training. He continued his career at the University of Milan and, since 2000 also at IFOM. Prof Marco has studied different cellular processes (translational, chromosome replication, DNA recombination, DNA repair, DNA topology and nuclear envelope dynamics) and regulatory pathways (translational control, cell cycle, checkpoint, gene gating) using a variety of approaches (biochemical, genetic, imaging, genomic, molecular biology). His major contributions are within the fields of chromosome dynamics and genome integrity. His work has contributed to elucidate the ATR and ATM-dependent checkpoint processes controlling the interfaces between DNA replication, recombination, transcription and DNA topology and preventing abnormal chromosome transitions. In recent years, he has been studying the connections between cell metabolism and genome integrity pathways and between chromosome dynamics and mechano-transduction circuits controlling cell and nuclear plasticity. An Integrated Mechano-Response Mediated By ATR And ATM ATM and ATR DNA damage response (DDR) kinases contain elastic domains. ATR protects nuclear integrity by controlling nuclear envelope elasticity in response to mechanical stress. ATR defects lead to nuclear envelope ruptures, leakage of nuclear DNA into the cytosol and activation of the cGAS/Sting immunity response. Using in vivo imaging, electron microscopy, proteomic and mechanobiology approaches we studied how ATM responds to mechanical stress. We report that cytoskeleton and ROS, but not DNA damage, nor Mre11, mediate ATM activation following cell deformation. ATM deficiency causes hyper-stiffness, stress fiber accumulation, YAP nuclear enrichment, plasma and nuclear membrane alterations during interstitial migration, and H3 hypermethylation. ATM locates to actin cytoskeleton and, following cytoskeleton stress, promotes recovery by phosphorylating key cytoskeleton and chromatin regulators. Our data contribute to explain some clinical features of A-T patients and pinpoint the existence of an integrated mechano-response in which ATM and ATR have distinct roles, unrelated to their canonical DDR functions. P 27 EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING Prof. Ming Lei DIRECTOR Shanghai Institute of Precision Medicine, Shanghai Jiao Tong University School of Medicine Dr. Ming Lei graduated from the Department of Physics of Tsinghua University in 1994, received a master degree of Physics from Department of Physics of McGill University in 1996 and a doctor degree of Biophysics from Harvard University in 2001. Between 2001 and 2004, he received postdoctoral training at the Department of Chemistry and Biochemistry of University of Colorado. From 2004 to 2011, Dr. Lei has been a professor at the Department of Biological Chemistry, University of Michigan. From 2011 to 2017, he was the Deputy Director of Shanghai Institute of Biochemistry and Cell Biology, and Director of National Center for Protein Science Shanghai. From 2017 to present, he is the Director of Shanghai Institute of Precision Medicine, Shanghai Jiao Tong University School of Medicine. The goal of Prof. Lei’s laboratory is to understand the organization and dynamics of macromolecular assemblies important for genome regulation and stability. With the combination of biophysics, biochemistry, cell biology and genetics approaches, his laboratory has made important progress on epigenetics and cancer biology. A Novel Primate-Specific X-Linked Amplicon Maintains Spermatogonia Self-Renewal And Genome Stability The X chromosome has been considered as a museum preserving ancestral gene contents since the proposal of the “Ohno’s law”. However, recent studies suggest the accelerated evolutionary rates of some X-linked loci, especially the amplicons with restricted expression in testis, and generally detected in cancers. The evolutionary origin of the ampliconic structures on the X chromosome and their relationship with male fertility remain to be unveiled. In this study, we identify a novel X-linked amplicon that was newly acquired in the primate lineage and derived from an ancient X-linked single-copy gene through a multi-step intergenic and intragenic duplication process. This primate-specific X-linked amplicon not only reveals restricted testis expression pattern, but also is highly enriched in the spermatogonial stem cells (SSCs) during spermatogenesis. We show that this amplicon is highly expressed in the transient amplifying SSCs instead of dormant SSCs. Our results indicate that this amplicon is essential to the SSC self-renewal by promoting proliferation, and to maintain the SSC genome stability through promoting HR-mediated DNA DSB repair. The identification of this novel X-linked amplicon and its vital role in the self-renewal and genome stability during spermatogenesis provides a new perspective to explain the long reproduction life and low germline mutation rate in humans. P 28 SESSION 3: DNA DAMAGE & AGING I SPEAKERS Prof. Brian Kennedy PROFESSOR / PROGRAMME DIRECTOR National University of Singapore Dr. Brian Kennedy is internationally recognized for his research in the basic biology of aging and as a visionary committed to translating research discoveries into new ways of detecting, delaying, preventing and treating human aging and associated diseases. He is a Distinguished Professor in Biochemistry and Physiology at the Yong Loo Lin School of Medicine at National University Singapore and serves as Director of (1) the Center for Healthy Longevity at the National University Health System, (2) the Healthy Longevity Translational Research Programme and (3) the Asian Center for Reproductive Longevity and Equality at NUS Medicine. Collectively, NUS aging research seeks to demonstrate that longevity interventions can be successfully employed in humans to extend healthspan, the disease-free and highly functional period of life. Pillars And Hallmarks Of Aging From The Perspective Of Longevity Interventions There is a growing sense that a holistic understanding of aging biology may be achievable. This would represent a tremendous advance in our collective biological understanding and afford opportunities for novel interventions to enhance human healthspan. Aging is the biggest risk factor for the major chronic diseases growing in prominence. These include cardiovascular and neurodegenerative diseases, diabetes and cancer. If aging can be slowed, the effect would be simultaneous protection from many of the chronic diseases. One strategy is to use animal model organisms to find common pathways that modulate aging and then to seek methods for their manipulation in humans. The TOR pathway is one point of convergence and a clinically approved drug targeting the TOR kinase, rapamycin, extends murine lifespan and healthspan. Many more small molecules are being added to the list of anti-ageing compounds. Here, I will discuss known and novel small molecule interventions, including natural products, and focusing on healthspan. It is critical to understand the mechanisms by which these interventions delay aging. We are now entering a stage in aging research where it is imperative to test aging interventions in humans. The potential to directly impact human healthspan is emerging from aging research and this approach, if successful, will have global impact. I will also discuss the strategies being employed to validate whether interventions slow or reverse human aging. P 29 EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING P 30 Session 4 DNA Damage & Aging II Chaired by: Eric Gilson SESSION 4: DNA DAMAGE & AGING II SPEAKERS Prof. Jing Ye VICE DIRECTOR Personalized Aging Medicine Center, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China The goal of Prof. Jing Ye is to lead the study of telomeres in aging research and medical practice. During her early career as a researcher, Prof. Jing Ye identified a crucial role of the shelterin protein TRF2 during telomere replication. This was followed by unexpected results pointing to “non canonical” roles of the same protein in neuronal gene expression and function. These seminal discoveries contributed to the concept of tissue-specific signaling of telomere dysfunction. Her current work is devoted to understanding how these pathways shape systemic aging. As a clinical doctor, Prof. Jing Ye makes a substantial effort to translate her results in clinic, particularly by the development of innovative telomere assays to screen compounds preventing the installation of neurodegenerative and metabolic disorders in the aging population. The Evolutionary Trajectory Of Telomeric Protective Proteins In Zebrafish Shelterin is a protein complex that binds and protects telomeres in a great variety of organisms. It counteracts at various levels the DNA damage response at chromosome ends through the specific function of each of its subunits. In vertebrates, shelterin is composed of six subunits, TRF1, TRF2, RAP1, TIN2, TPP1 and POT1 that can function as a full complex or as subcomplexes. Their essential role in telomere maintenance together with their declining expression during aging suggest that they are key drivers of the aging process. We generated a series of shelterin subunit mutated zebrafish by a CRISPR/Cas9 RNA-guided system. We have revealed among them different patterns of chromosome binding sites, telomere protection properties and functions during development and aging. We propose a model of telomere evolution based on the redeployment of general factors involved in genome maintenance, coupling telomere status to development and aging. P 33 EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING Dr. Sophie Postel-Vinay CLINICIAN SCIENTIST Institut Gustave Roussy Sophie Postel-Vinay (MD, Ph.D), is currently Physician Scientist, senior medical oncologist at the Drug Development Department and Group Leader at the U981 INSERM research unit of Gustave Roussy. Specialized in Drug Development and early phase clinical trials, she completed her medical oncology residency training in Paris and at the Royal Marsden Hospital of London at the Drug Development Unit. She was the head of the Phase 1 committee between 2020 and 2022, and is particularly interested in novel designs and dose-definition in phase 1 trials. Through her Physician Scientist position, Dr Postel-Vinay also has a fundamental and translational research activity within the INSERM Unit 981. She obtained in 2017 the ATIP-Avenir “Young Group Leader” grant from INSERM, which allowed her to develop her own independent group. Her current research activity focuses on chromatin remodeling and its interplay with DNA repair and immune modulation in solid tumors. Harnessing Genetic Vulnerabilities In Immuno-Oncology: Novel Therapeutic Opportunities Synthetic lethality has traditionally been used to selectively kill DNA damage response (DDR)- deficient cells. Over the past few years, it has become increasingly evident that the DDR also influences tumor cell immunogenicity, but how this interplay could be harnessed to improve the treatment of cancer remains elusive. In this talk, I will describe our recent findings on how DDR inhibitors not only selectively elicit synthetic lethality, but also modulate tumor cell immunogenicity in specific DDR- and chromatin remodeling-defective contexts. I will further present the academic proof-of-concept studies that were developed on the basis of these laboratory results, and provide perspectives on reciprocal “bedside-to-bench” translational research performed on patient biopsies. P 34 SESSION 4: DNA DAMAGE & AGING II SPEAKERS Prof. James Chen PROFESSOR HHMI; University of Texas Southwestern Medical Center Zhijian ‘James’ Chen is an Investigator of Howard Hughes Medical Institute, and Professor in the Department of Molecular Biology at the University of Texas Southwestern Medical Center at Dallas. Prior to moving to Dallas, Chen was a senior scientist at ProScript Inc. where he helped discover the proteasome inhibitor VELCADE, a medicine used for the treatment of multiple myeloma. After joining UT Southwestern in 1997, Chen discovered the regulatory role of ubiquitination in protein kinase activation in the NF-kB and MAP kinase pathways. In addition, he discovered the Mitochondrial Antiviral Signaling (MAVS) protein that reveals a new role of mitochondria in immunity. More recently, Chen discovered cyclic GMP-AMP synthase (cGAS) as a cytosolic DNA sensor and a new cyclic di-nucleotide signaling pathway that mediates innate immune responses in animal cells. For his work, Chen has received numerous honors including the National Academy of Science (NAS) Award in Molecular Biology (2012), election to the NAS (2014), the Lurie Prize in Biomedical Sciences from the Foundation of NIH (2018), the Breakthrough Prize in Life Sciences (2019), the Switzer Prize (2019) and the William B. Coley Award for Distinguished Research in Basic and Tumor Immunology (2020). Igniting An Immune Response To DNA With cGAS DNA entering the cytoplasm of mammalian cells is a danger signal that triggers a potent innate immune response, including the production of type-I interferons and inflammatory cytokines. We have identified the enzyme cGAS as the sensor of cytosolic DNA that triggers the innate immune response. cGAS catalyzes the synthesis of cyclic GMP-AMP (cGAMP), which functions as a second messenger that activates the adaptor protein STING and the downstream pathway. The cGAS- STING pathway plays a critical role in immune defense, cellular senescence, autoimmune diseases and cancer. As such, this pathway must be tightly regulated. I will discuss our recent work on the regulation of the cGAS-STING pathway. P 35 EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING Prof. Hyeseong Cho PROFESSOR Ajou University School of Medicine Hyeseong Cho received her B.S in Biology from Yonsei University, Korea and then completed her Ph.D. in Physiology from University of Illinois at Urbana-Champaign, USA in 1992. After postdoctoral training in NIH, she joined the Ajou University School of Medicine in 1994 as a faculty member. During her academic career, she has led the “Genomics Instability Research Center” as a director (2011-2018), and published over 90 publications. She studies molecular mechanisms on genome integrity and mitochondria-mediated signaling. Her group discovered that RSF1 (Remodeling and Spacing Factor1) not only promotes the DNA damage response (DDR) signaling, but also plays an essential role in the maintenance of mitotic fidelity. In addition, she found that cells efficiently integrate the nuclear DDR signal from the cytoplasm and mitochondria against genotoxic stress. DNA Damage Response and Mitochondrial Dynamics Cells are constantly challenged by genotoxic stresses and integrity of the nuclear genome is preserved by the DNA damage response (DDR) and repair. Additionally, these stresses can induce mitochondria to transiently hyperfuse; however, it remains unclear whether canonical DDR is linked to these mitochondrial morphological changes. Here, we report that the abolition of mitochondrial fusion causes a substantial defect in the ATM-mediated DDR signaling. This deficiency is overcome by the restoration of mitochondria fusion. In cells with fragmented mitochondria, genotoxic stress-induced activation of JNK and its translocation to DNA lesion are lost. Importantly, the mitochondrial fusion machinery of MFN1/MFN2 associates with Sab (SH3BP5) and JNK, and these interactions are indispensable for the Sab-mediated activation of JNK and the ATM-mediated DDR signaling. Accordingly, the formation of BRCA1 and 53BP1 foci, as well as homology and end-joining repair are impaired in cells with fragmented mitochondria. Together, these data show that mitochondrial fusion-dependent JNK signaling is essential for the DDR, providing vital insight into the integration of nuclear and cytoplasmic stress signals. P 36 SESSION 4: DNA DAMAGE & AGING II SPEAKERS Prof. Eiji Hara PROFESSOR Osaka University Eiji Hara obtained his Ph.D. at the Tokyo University of Science in 1993 and moved to the Lawrence Berkeley Laboratory (Berkeley, USA) as a Postdoctoral Fellow to work with Dr. Judith Campisi. In 1995, he joined the Imperial Cancer Research Fund laboratories (London, UK) as a Postdoctoral Fellow to work with Dr. Gordon Peters, and then became a Group Leader at the Cancer Research UK Paterson Institute for Cancer Research (Manchester, UK) in 1998. In 2003, he returned to Japan as a Professor at the University of Tokushima (Tokushima, Japan) and moved to the Japanese Foundation for Cancer Research (Tokyo, Japan) as a Division Chief in 2008. In 2015, he moved to Osaka University (Osaka, Japan) as a professor. Cellular Senescence And Cancer: Relevance To Microorganisms Although cellular senescence acts as an important tumor suppression mechanism, the accumulation of senescent cells in vivo has been shown to cause a phenomenon called SASP, in which various pro-inflammatory and/or pro-tumorigenic factors are secreted, resulting in harmful side effects. It is therefore conceivable that the accumulation of senescent cells in vivo may contribute to aging- associated inflammatory diseases, such as cancer. Thus, the development of methods to remove senescent cells accumulated in the body as a means of tumor suppression and anti-aging has been actively pursued, and more than 20 candidates for senescent cell removal drugs (senolytic drugs) have already been reported so far. On the other hand, it has been reported that SASP may play important roles in wound healing, immune activation, and other aspects of homeostasis in the body. Therefore, rather than eliminating senescent cells accumulated in the body, we thought it would be safer and more effective to identify the causes of cellular senescence in the body and prevent them. Here, we will focus on changes in the gut microflora as one of the causes of cellular senescence and discuss their mechanism of action. P 37 EMBO WORKSHOP 2022 THE DNA DAMAGE RESPONSE, IMMUNITY AND AGING P 38 Session 5 DNA Damage & Aging III Chaired by: Hyunsook Lee