Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY, USA.
Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, HHMI, Boston, MA, USA.
Cell Cycle. 2023 Feb;22(4):379-389. doi: 10.1080/15384101.2022.2123886. Epub 2022 Oct 7.
DNA double-strand breaks (DSBs) pose a major threat to the genome, so the efficient repair of such breaks is essential. DSB processing and repair is affected by 53BP1, which has been proposed to determine repair pathway choice and/or promote repair fidelity. 53BP1 and its downstream effectors, RIF1 and shieldin, control 3' overhang length, and the mechanism has been a topic of intensive research. Here, we highlight recent evidence that 3' overhang control by 53BP1 occurs through fill-in synthesis of resected DSBs by CST/Polα/primase. We focus on the crucial role of fill-in synthesis in BRCA1-deficient cells treated with PARPi and discuss the notion of fill-in synthesis in other specialized settings and in the repair of random DSBs. We argue that - in addition to other determinants - repair pathway choice may be influenced by the DNA sequence at the break which can impact CST binding and therefore the deployment of Polα/primase fill-in.
DNA 双链断裂（DSBs）对基因组构成重大威胁，因此高效修复这些断裂至关重要。53BP1 影响 DSB 的处理和修复，它被认为可以决定修复途径的选择和/或促进修复保真度。53BP1 及其下游效应因子 RIF1 和 shieldin 控制 3'突出端的长度，该机制一直是密集研究的主题。在这里，我们强调最近的证据表明，53BP1 通过 CST/Polα/引物酶对切除的 DSB 进行填充合成来控制 3'突出端。我们专注于填充合成在 PARPi 处理的 BRCA1 缺陷细胞中的关键作用，并讨论在其他特殊环境中和随机 DSB 修复中填充合成的概念。我们认为 - 除其他决定因素外 - 修复途径的选择可能受到断裂处 DNA 序列的影响，这可能会影响 CST 的结合，从而影响 Polα/引物酶的填充合成。
