范科尼贫血
顺铂
生物
磷酸化
DNA复制
癌症研究
信号转导
细胞生物学
作者
Yi Zhang,Jing Li,Yuan Zhou,Zhuqing Li,Changmin Peng,Huadong Pei,Wenge Zhu
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2022-07-22
标识
DOI:10.1158/0008-5472.can-22-0769
摘要
Abstract The Fanconi anemia (FA) pathway is essential for repairing DNA inter-strand crosslinks (ICL). ICLs induce stalled DNA replication forks and trigger activation of the FA pathway by promoting recruitment of the FANCM/FAAP24/MHF complex to ICL sites. Given that stalled replication forks are proximal to ICL sites, fork-associated proteins may coordinate with FA factors to rapidly sense ICLs for activation of FA signaling. Here we report that And-1, a replisome protein, is critical for activation of the FA pathway by sensing ICL-stalled forks and recruiting the FANCM/FAAP24 complex to ICLs. In response to ICLs, And-1 rapidly accumulated at ICL-stalled forks in a manner dependent on ATR-induced phosphorylation at T826. And-1 phosphorylation triggered an intramolecular change that promoted the interaction of And-1 with FANCM/FAAP24, resulting in recruitment of the FANCM/FAAP24 complex to ICLs. Furthermore, p-T826 And-1 was elevated in cisplatin-resistant ovarian cancer cells, and activated And-1 contributed to cisplatin resistance. Collectively, these studies elucidate a mechanism by which And-1 regulates FA signaling and identify And-1 as a potential target for developing therapeutic approaches to treat platinum-resistant ovarian cancer.
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