端粒
生物
RAD52
细胞生物学
端粒酶
遗传学
DNA
DNA修复
基因
雷达51
作者
Tribhuwan Yadav,Jiamin Zhang,Jie Ouyang,Wendy Leung,Antoine Simoneau,Lee Zou
出处
期刊:Molecular Cell
[Elsevier]
日期:2022-11-01
卷期号:82 (21): 3985-4000.e4
被引量:16
标识
DOI:10.1016/j.molcel.2022.09.026
摘要
•TERRA and RAD51AP1 contribute to the ALT activity in RAD52 KO cells •RAD51AP1 promotes telomeric R-loop formation in vitro and in ALT+ cells •Telomeric R-loops increase G4s at telomeres and are dynamic in cells •Telomeric G4s persist without R-loops and enable D-loop formation without RAD52 Alternative lengthening of telomeres (ALT), a telomerase-independent process maintaining telomeres, is mediated by break-induced replication (BIR). RAD52 promotes ALT by facilitating D-loop formation, but ALT also occurs through a RAD52-independent BIR pathway. Here, we show that the telomere non-coding RNA TERRA forms dynamic telomeric R-loops and contributes to ALT activity in RAD52 knockout cells. TERRA forms R-loops in vitro and at telomeres in a RAD51AP1-dependent manner. The formation of R-loops by TERRA increases G-quadruplexes (G4s) at telomeres. G4 stabilization enhances ALT even when TERRA is depleted, suggesting that G4s act downstream of R-loops to promote BIR. In vitro, the telomeric R-loops assembled by TERRA and RAD51AP1 generate G4s, which persist after R-loop resolution and allow formation of telomeric D-loops without RAD52. Thus, the dynamic telomeric R-loops formed by TERRA and RAD51AP1 enable the RAD52-independent ALT pathway, and G4s orchestrate an R- to D-loop switch at telomeres to stimulate BIR. Alternative lengthening of telomeres (ALT), a telomerase-independent process maintaining telomeres, is mediated by break-induced replication (BIR). RAD52 promotes ALT by facilitating D-loop formation, but ALT also occurs through a RAD52-independent BIR pathway. Here, we show that the telomere non-coding RNA TERRA forms dynamic telomeric R-loops and contributes to ALT activity in RAD52 knockout cells. TERRA forms R-loops in vitro and at telomeres in a RAD51AP1-dependent manner. The formation of R-loops by TERRA increases G-quadruplexes (G4s) at telomeres. G4 stabilization enhances ALT even when TERRA is depleted, suggesting that G4s act downstream of R-loops to promote BIR. In vitro, the telomeric R-loops assembled by TERRA and RAD51AP1 generate G4s, which persist after R-loop resolution and allow formation of telomeric D-loops without RAD52. Thus, the dynamic telomeric R-loops formed by TERRA and RAD51AP1 enable the RAD52-independent ALT pathway, and G4s orchestrate an R- to D-loop switch at telomeres to stimulate BIR. RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRAKaminski et al.Molecular CellOctober 19, 2022In BriefKaminski et al. show the cooperative roles of RAD51AP1 and TERRA in generating HR intermediates during ALT-HDR. Proteomic analyses uncover that RAD51AP1 binding of R-loops might serve to maintain chromatin that suppresses TERRA and prevents transcription-replication collisions (TRCs) during ALT-HDR. Full-Text PDF Open Access
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