端粒
染色质
生物
抄写(语言学)
细胞生物学
DNA
机制(生物学)
计算生物学
遗传学
物理
量子力学
语言学
哲学
作者
Nicole Kaminski,Anne R. Wondisford,Youngho Kwon,Michelle Lee Lynskey,Ragini Bhargava,Jonathan Barroso-González,Laura García-Expósito,Boxue He,Meng Xu,Dattatreya Mellacheruvu,Simon C. Watkins,Mauro Modesti,Kyle M. Miller,Alexey I. Nesvizhskii,Huaiying Zhang,Patrick Sung,Roderick J. O’Sullivan
出处
期刊:Molecular Cell
[Elsevier]
日期:2022-11-01
卷期号:82 (21): 4001-4017.e7
被引量:22
标识
DOI:10.1016/j.molcel.2022.09.025
摘要
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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