DDX11 loss causes replication stress and pharmacologically exploitable DNA repair defects.
DDX11 loss causes replication stress and pharmacologically exploitable DNA repair defects.
复制标题
DDX11缺失导致复制应激和不可利用的DNA修复缺陷。
DOI：
10.1073/pnas.2024258118
复制
发表时间：
2021-04-27
影响因子：
11.1
通讯作者：
Branzei D
中科院分区：
文献类型：
--
作者：
Jegadesan NK;Branzei D
复制压力会影响发育，是癌症的一个标志。华沙断裂综合征是一种由保守的DDX11 DNA解旋酶突变引起的发育障碍。在此，利用DDX11缺陷的人类细胞模型，我们报道了DDX11解旋酶可以防止复制应激，并通过同源重组介导同源定向修复。在机制上，DDX11促进切除，使RPA和RAD51聚焦形成，并与RAD51介质BRCA1和BRCA2无冗余作用。因此，靶向DDX11可以提高化疗敏感性和耐药brca1 /2突变癌症的化疗反应性，这些癌症通过抑制突变或体细胞逆转恢复了同源重组能力。结果指出DDX11是一个关键的复制应激缓解因子，其靶向可以改善一系列癌症的化疗反应。DDX11编码一种铁硫簇DNA解旋酶，这是癌症发生、突变和过度表达所必需的。在这里，我们发现DDX11的缺失会导致复制应激，并使癌细胞对DNA损伤剂敏感，包括聚ADP核糖聚合酶（PARP）抑制剂和铂类药物。我们发现DDX11解旋酶活性阻止化疗药物过敏和DNA损伤的积累。在机制上，DDX11作用于53BP1的下游，介导同源性定向修复和RAD51焦点形成，其方式与BRCA1和BRCA2不重复。因此，DDX11下调加重了brca1 /2突变癌症的化疗敏感性，并使化疗耐药的brca1 /2突变癌细胞重获同源重组能力。结果进一步表明，DDX11通过协助双链断裂切除和RPA和RAD51在单链DNA底物上的负载来促进重组修复。我们提出DDX11作为癌症的潜在靶点，通过创造药理学上可利用的DNA修复漏洞。
Replication stress can affect development and is a hallmark of cancers. Warsaw breakage syndrome is a developmental disorder caused by mutations in the conserved DDX11 DNA helicase. Here, using human cellular models of DDX11 deficiency, we report that DDX11 helicase prevents replication stress and mediates homology-directed repair via homologous recombination. Mechanistically, DDX11 promotes resection, enabling RPA and RAD51 focus formation, and acts nonredundantly with the RAD51 mediators BRCA1 and BRCA2. As a result, targeting DDX11 confers improved chemotherapy responsiveness in both chemotherapy-sensitive and drug-resistant BRCA1/2-mutated cancers that regained homologous recombination proficiency by suppressor mutation or somatic reversion. The results pinpoint DDX11 as a critical replication stress mitigating factor whose targeting can improve chemotherapeutic response in a range of cancers. DDX11 encodes an iron–sulfur cluster DNA helicase required for development, mutated, and overexpressed in cancers. Here, we show that loss of DDX11 causes replication stress and sensitizes cancer cells to DNA damaging agents, including poly ADP ribose polymerase (PARP) inhibitors and platinum drugs. We find that DDX11 helicase activity prevents chemotherapy drug hypersensitivity and accumulation of DNA damage. Mechanistically, DDX11 acts downstream of 53BP1 to mediate homology-directed repair and RAD51 focus formation in manners nonredundant with BRCA1 and BRCA2. As a result, DDX11 down-regulation aggravates the chemotherapeutic sensitivity of BRCA1/2-mutated cancers and resensitizes chemotherapy drug–resistant BRCA1/2-mutated cancer cells that regained homologous recombination proficiency. The results further indicate that DDX11 facilitates recombination repair by assisting double strand break resection and the loading of both RPA and RAD51 on single-stranded DNA substrates. We propose DDX11 as a potential target in cancers by creating pharmacologically exploitable DNA repair vulnerabilities.