RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Molecular Cell Year : 2022

RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA


Alternative lengthening of telomeres (ALT) is a homology-directed repair (HDR) mechanism of telomere elongation that controls proliferation in subsets of aggressive cancer. Recent studies have revealed that telomere repeat-containing RNA (TERRA) promotes ALT-associated HDR (ALT-HDR). Here, we report that RAD51AP1, a crucial ALT factor, interacts with TERRA and utilizes it to generate D- and R-loop HR intermediates. We also show that RAD51AP1 binds to and might stabilize TERRA-containing R-loops as RAD51AP1 depletion reduces R-loop formation at telomere DNA breaks. Proteomic analyses uncover a role for RAD51AP1-mediated TERRA R-loop homeostasis in a mechanism of chromatin-directed suppression of TERRA and prevention of transcription-replication collisions (TRCs) during ALT-HDR. Intriguingly, we find that both TERRA binding and this non-canonical function of RAD51AP1 require its intrinsic SUMO-SIM regulatory axis. These findings provide insights into the multi-contextual functions of RAD51AP1 within the ALT mechanism and regulation of TERRA.
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Dates and versions

inserm-03825785 , version 1 (23-10-2022)



Nicole Kaminski, Anne Wondisford, Youngho Kwon, Michelle Lee Lynskey, Ragini Bhargava, et al.. RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA. Molecular Cell, 2022, S1097-2765 (22), pp.00935-2. ⟨10.1016/j.molcel.2022.09.025⟩. ⟨inserm-03825785⟩
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