Dissection of non-canonical DNA damage response mechanisms controlling the senescence program

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Cellular senescence is a natural cell aging mechanism occurring in response to unrepaired genomic DNA damage caused by conditions like dysfunctional telomeres or chronic oxidative stress. Senescent cells are characterized by a senescence¬-associated stable proliferation arrest (SAPA) and by a secretory phenotype (SASP) that contribute to tissue remodeling during normal tissue repair or development. We and others have shown that the senescence program is controlled by the DNA damage response (DDR), which is an interlaced network of signalling pathways activated by DNA double-strand breaks (DSB). It remains unclear why and how the DDR, which is activated within minutes of a DSB (canonical response), establishes proliferation arrest rapidly via cell cycle checkpoints, but takes day to establish the stable SAPA and SASP. To understand the transition between the early canonical DDR and a potentially persistent DDR we developed longitudinal models of DNA damage-¬induced senescence via irradiation or controlled telomere uncapping in normal human cells. We discovered that telomere dysfunction triggers a rapid focal DDR activity accompanied by a transient cell cycle arrest, which is rapidly bypassed via DNA damage tolerance. Replicated dysfunctional telomeres then result in homologous recombination¬-mediated telomeric sister chromatid fusions underlying next mitosis genome instability. We also showed that a noncanonical DDR occurs several days following DNA damage induction and is characterized by a progressive accumulation of DDR components like ATM and the MRN complex on the chromatin. Our hypothesis is that the SAPA and the SASP require delayed alternative DDR activities when compared to the immediate canonical DDR involved in DNA repair and transient cell cycle arrest, a phenomenon we term non¬canonical DDR. The long-term objective of this research program is to characterize and define non¬canonical DDR signaling via the identification of the molecular regulators involved in this process and the evaluation of their impact on SAPA or SASP. Our specific short-term objectives are to characterize this novel non¬canonical DDR using a mix of targeted and unbiased strategies. We will identify the interactome and molecular regulators of non-canonical DDR signaling at the protein and chromatin/transcriptional level to understand the role of this network in establishing and maintaining senescence. Understanding the role and activities of the DDR remain one of the major current challenge in fundamental genome stability cell biology, the proposed research program will further describe a novel non¬canonical DDR network interlaced within genome stability and the establishment of cell senescence. This program will attract HQP to this cutting-edge research subject in a way that promote EDI and will train them with a variety of multidisciplinary skills.