FANCM and FAAP24 Function in ATR-Mediated Checkpoint Signaling Independently of the Fanconi Anemia Core Complex
FANCM and FAAP24 Function in ATR-Mediated Checkpoint Signaling Independently of the Fanconi Anemia Core Complex
复制标题
DOI：
10.1016/j.molcel.2008.10.014
复制
发表时间：
2008-11-07
期刊：
影响因子：
16
通讯作者：
Boulton, Simon J.
中科院分区：
文献类型：
--
作者：
Collis, Spencer J.;Ciccia, Alberto;Boulton, Simon J.
范可尼贫血（FA）通路与DNA修复和癌症易感性有关。该途径的中心是FA核心复合物，其在复制应激后通过FANCM和FAAP 24靶向染色质。在这里，我们表明，FANCM和FAAP 24相互作用的检查点蛋白HCLK 2独立的FA核心复合物。除了FA通路激活缺陷外，FANCM或FAAP 24的下调还损害ATR/Chk 1介导的检查点信号传导，导致Chk 1、p53和FANCE磷酸化缺陷; 53 BP 1病灶形成;和Cdc 25 A降解。因此，FANCM和FAAP 24缺陷导致内源性DNA损伤增加，并且不能有效地引发细胞周期检查点反应。此外，我们发现，FANCM的DNA移位酶活性，这是FA途径激活所必需的，其在ATR/Chk 1信号传导中的作用。我们的数据表明，FANCM和FAAP 24的DNA损伤识别和重塑活动与ATR/Chkl合作，以促进DNA损伤检查点的有效激活。
The Fanconi anemia (FA) pathway is implicated in DNA repair and cancer predisposition. Central to this pathway is the FA core complex, which is targeted to chromatin by FANCM and FAAP24 following replication stress. Here we show that FANCM and FAAP24 interact with the checkpoint protein HCLK2 independently of the FA core complex. In addition to defects in FA pathway activation, downregulation of FANCM or FAAP24 also compromises ATR/Chk1-mediated checkpoint signaling, leading to defective Chk1, p53, and FANCE phosphorylation; 53BP1 focus formation; and Cdc25A degradation. As a result, FANCM and FAAP24 deficiency results in increased endogenous DNA damage and a failure to efficiently invoke cell-cycle checkpoint responses. Moreover, we find that the DNA translocase activity of FANCM, which is dispensable for FA pathway activation, is required for its role in ATR/Chk1 signaling. Our data suggest that DNA damage recognition and remodeling activities of FANCM and FAAP24 cooperate with ATR/Chkl to promote efficient activation of DNA damage checkpoints.