TFIP11 promotes replication fork reversal to preserve genome stability
TFIP11 promotes replication fork reversal to preserve genome stability
复制标题
DOI：
10.1038/s41467-024-45684-3
复制
发表时间：
2024-02-10
影响因子：
16.6
通讯作者：
Liu，Ting
中科院分区：
文献类型：
--
作者：
Chen，Junliang;Wu，Mingjie;Liu，Ting
复制叉逆转是高等真核细胞对抗复制应激的重要保护机制，是通过一系列协调的酶促反应来协调的。Bloom综合征基因产物BLM是高度保守的RecQ解旋酶家族的一员，与此过程有关，但其精确调控和作用仍知之甚少。在这项研究中，我们证明，GCFC结构域的蛋白TFIP 11形成一个复杂的BLM解旋酶。TFIP 11表现出对结合DNA底物的偏好，所述DNA底物模拟在停滞的复制叉处产生的结构。TFIP11或BLM的缺失导致另一种蛋白质在停滞的分叉处积累。这种异常的积累，反过来，损害RAD51介导的叉逆转和减缓，敏感细胞复制应激诱导剂，并增强染色体不稳定性。这些发现揭示了一种以前未鉴定的调节机制，该机制调节BLM和RAD 51在停滞叉处的活性，从而影响基因组完整性。
Replication fork reversal, a critical protective mechanism against replication stress in higher eukaryotic cells, is orchestrated via a series of coordinated enzymatic reactions. The Bloom syndrome gene product, BLM, a member of the highly conserved RecQ helicase family, is implicated in this process, yet its precise regulation and role remain poorly understood. In this study, we demonstrate that the GCFC domain-containing protein TFIP11 forms a complex with the BLM helicase. TFIP11 exhibits a preference for binding to DNA substrates that mimic the structure generated at stalled replication forks. Loss of either TFIP11 or BLM leads to the accumulation of the other protein at stalled forks. This abnormal accumulation, in turn, impairs RAD51-mediated fork reversal and slowing, sensitizes cells to replication stress-inducing agents, and enhances chromosomal instability. These findings reveal a previously unidentified regulatory mechanism that modulates the activities of BLM and RAD51 at stalled forks, thereby impacting genome integrity.