Department of Biochemistry Indian Institute of Science, Bangalore 560012, India.
Applied Genomics Section, Bioscience Group, Bhabha Atomic Research Centre, Mumbai 400085, India.
Cell Rep. 2024 Aug 27;43(8):114594. doi: 10.1016/j.celrep.2024.114594. Epub 2024 Aug 6.
Homologous recombination (HR) plays an essential role in the repair of DNA double-strand breaks (DSBs), replication stress responses, and genome maintenance. However, unregulated HR during replication can impair genome duplication and compromise genome stability. The mechanisms underlying HR regulation during DNA replication are obscure. Here, we find that RTEL1 helicase, RAD51, and RAD51 paralogs are enriched at stalled replication sites. The absence of RTEL1 leads to an increase in the RAD51-mediated HR and fork reversal during replication and affects genome-wide replication, which can be rescued by co-depleting RAD51 and RAD51 paralogs. Interestingly, co-depletion of fork remodelers such as SMARCAL1/ZRANB3/HLTF/FBH1 and expression of HR-defective RAD51 mutants also rescues replication defects in RTEL1-deficient cells. The anti-recombinase function of RTEL1 during replication depends on its interaction with PCNA and helicase activity. Together, our data identify the role of RTEL1 helicase in restricting RAD51-mediated fork reversal and HR activity to facilitate error-free genome duplication.
同源重组（HR）在 DNA 双链断裂（DSB）的修复、复制应激反应和基因组维护中起着至关重要的作用。然而，复制过程中不受调节的 HR 会损害基因组复制并影响基因组稳定性。HR 在 DNA 复制过程中调节的机制尚不清楚。在这里，我们发现 RTEL1 解旋酶、RAD51 和 RAD51 同源物在停滞的复制位点富集。RTEL1 的缺失会导致 RAD51 介导的 HR 和复制过程中的叉反转增加，并影响全基因组复制，RAD51 和 RAD51 同源物的共缺失可以挽救这一现象。有趣的是，叉重排因子如 SMARCAL1/ZRANB3/HLTF/FBH1 的共缺失以及 HR 缺陷 RAD51 突变体的表达也可以挽救 RTEL1 缺陷细胞中的复制缺陷。复制过程中 RTEL1 的抗重组功能依赖于其与 PCNA 的相互作用和解旋酶活性。总之，我们的数据确定了 RTEL1 解旋酶在限制 RAD51 介导的叉反转和 HR 活性以促进无错误基因组复制中的作用。
