Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9RQ, UK.
Friedrich Miescher Institute for Biomedical Research, 4058, Basel, Switzerland.
Curr Genet. 2020 Dec;66(6):1085-1092. doi: 10.1007/s00294-020-01106-7. Epub 2020 Sep 9.
The disease-associated nuclease-helicase DNA2 has been implicated in DNA end-resection during DNA double-strand break repair, Okazaki fragment processing, and the recovery of stalled DNA replication forks (RFs). Its role in Okazaki fragment processing has been proposed to explain why DNA2 is indispensable for cell survival across organisms. Unexpectedly, we found that DNA2 has an essential role in suppressing homologous recombination (HR)-dependent replication restart at stalled RFs. In the absence of DNA2-mediated RF recovery, excessive HR-restart of stalled RFs results in toxic levels of abortive recombination intermediates that lead to DNA damage-checkpoint activation and terminal cell-cycle arrest. While HR proteins protect and restart stalled RFs to promote faithful genome replication, these findings show how HR-dependent replication restart is actively constrained by DNA2 to ensure cell survival. These new insights disambiguate the effects of DNA2 dysfunction on cell survival, and provide a framework to rationalize the association of DNA2 with cancer and the primordial dwarfism disorder Seckel syndrome based on its role in RF recovery.
疾病相关的核酸酶解旋酶 DNA2 已被牵涉到 DNA 双链断裂修复、冈崎片段处理以及停滞的 DNA 复制叉（RFs）恢复过程中的 DNA 末端切除。其在冈崎片段处理中的作用被认为可以解释为什么 DNA2 在生物体内对细胞存活是不可或缺的。出乎意料的是，我们发现 DNA2 在抑制同源重组（HR）依赖性复制起始方面对于停滞的 RFs 具有至关重要的作用。如果没有 DNA2 介导的 RF 恢复，停滞的 RFs 中过多的 HR 起始会导致大量的无效重组中间体，从而导致 DNA 损伤检查点激活和细胞周期末端停滞。虽然 HR 蛋白可以保护和重新启动停滞的 RFs，以促进忠实的基因组复制，但这些发现表明 HR 依赖性复制起始如何被 DNA2 主动限制，以确保细胞存活。这些新的见解澄清了 DNA2 功能障碍对细胞存活的影响，并为根据其在 RF 恢复中的作用来合理化 DNA2 与癌症和原始矮小症疾病 Seckel 综合征之间的关联提供了一个框架。
