TERRA 和 RAD51AP1 通过 R 环到 D 环转换促进端粒的替代性延长。
TERRA and RAD51AP1 promote alternative lengthening of telomeres through an R- to D-loop switch.
机构信息
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
出版信息
Mol Cell. 2022 Nov 3;82(21):3985-4000.e4. doi: 10.1016/j.molcel.2022.09.026. Epub 2022 Oct 19.
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.
端粒的非编码 RNA TERRA 形成动态的端粒 R 环，并有助于 RAD52 缺失细胞中的 ALT 活性。TERRA 在体外和 RAD51AP1 依赖性方式下在端粒处形成 R 环。TERRA 形成的 R 环增加了端粒上的 G-四联体 (G4s)。即使耗尽 TERRA，G4 的稳定也能增强 ALT，表明 G4s 作为 R 环的下游发挥作用，以促进 BIR。在体外，由 TERRA 和 RAD51AP1 组装的端粒 R 环产生 G4s，这些 G4s 在 R 环解析后仍然存在，并允许在没有 RAD52 的情况下形成端粒 D 环。因此，由 TERRA 和 RAD51AP1 形成的动态端粒 R 环使 RAD52 非依赖性 ALT 途径成为可能，并且 G4s 在端粒处协调 R 环到 D 环的转变，以刺激 BIR。
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