RAD54L regulates replication fork progression and nascent strand degradation in BRCA1/2-deficient cells.
RAD54L regulates replication fork progression and nascent strand degradation in BRCA1/2-deficient cells.
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RAD54L 调节 BRCA1/2 缺陷细胞中的复制叉进展和新生链降解。
DOI：
10.1101/2023.07.26.550704
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Wiese,Claudia
中科院分区：
文献类型：
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作者：
Uhrig,MollieE;Sharma,Neelam;Maxwell,Petey;Selemenakis,Platon;Wiese,Claudia
RAD 54 L是一种在同源重组DNA修复（HR）中具有关键作用的DNA马达蛋白。在体外，RAD 54 L也显示出催化模型复制叉的逆转和恢复。然而，很少有人知道RAD 54 L在调节细胞中DNA复制动力学中的作用。在这里，我们表明，RAD 54 L作为一个叉重塑和抑制人类细胞中的复制叉的进展。类似于HLTF和FBH 1，并且与叉逆转中的作用一致，RAD 54 L催化响应于复制应激的叉进展的减缓。在BRCA 1/2缺陷细胞中，RAD 54 L活性导致新生链DNA降解，并且RAD 54 L的缺失减少DNA双链断裂的形成。使用分离的功能突变，我们表明，RAD 54 L介导的叉约束取决于其催化分支迁移的能力。我们的研究结果揭示了RAD 54 L在调节细胞中复制叉动力学方面的新作用，并强调了RAD 54 L功能对BRCA 1/2缺陷型肿瘤患者治疗的影响。
RAD54L is a DNA motor protein with critical roles in homologous recombination DNA repair (HR). In vitro, RAD54L was also shown to catalyze the reversal and restoration of model replication forks. Little, however, is known about the role of RAD54L in regulating the dynamics of DNA replication in cells. Here, we show that RAD54L functions as a fork remodeler and restrains the progression of replication forks in human cells. Analogous to HLTF and FBH1, and consistent with a role in fork reversal, RAD54L catalyzes the slowing of fork progression in response to replication stress. In BRCA1/2-deficient cells, RAD54L activity leads to nascent strand DNA degradation, and loss of RAD54L reduces DNA double-strand break formation. Using a separation-of-function mutation, we show that RAD54L-mediated fork restraint depends on its ability to catalyze branch migration. Our results reveal a new role for RAD54L in regulating the dynamics of replication forks in cells and highlight the impact of RAD54L function on the treatment of patients with BRCA1/2-deficient tumors.