FANCD2 regulates BLM complex functions independently of FANCI to promote replication fork recovery
FANCD2 regulates BLM complex functions independently of FANCI to promote replication fork recovery
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DOI：
10.1093/nar/gkt348
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发表时间：
2013-07-01
影响因子：
14.9
通讯作者：
Sobeck, Alexandra
中科院分区：
文献类型：
--
作者：
Chaudhury, Indrajit;Sareen, Archana;Sobeck, Alexandra
范可尼贫血（FA）和布卢姆综合征共有重叠的表型，包括自发性染色体异常和增加的癌症易感性。FA蛋白途径包括上游核心复合物，其介导两个中心参与者FANCD 2和FANCI募集到停滞复制叉的位点。成功的分叉恢复取决于参与含有拓扑异构酶III α、RMI 1、RMI 2和复制蛋白A的较大蛋白质复合物（“BLMcx”）的布卢姆解旋酶BLM。我们表明，FANCD 2是BLMcx功能的重要调节因子：它保持BLM蛋白的稳定性，并对完整的BLMcx组装至关重要;此外，它招募BLMcx在正常的S期复制染色质，并介导BLMcx成员对DNA损伤的磷酸化。在复制应激期间，FANCD 2和BLM合作以促进停滞的复制叉的重新启动，同时抑制新的复制起点的激发。相比之下，FANCI对于FANCD 2依赖性BLMcx调节是稳定的，证明FANCD 2与FANCI的功能分离。
Fanconi Anemia (FA) and Bloom Syndrome share overlapping phenotypes including spontaneous chromosomal abnormalities and increased cancer predisposition. The FA protein pathway comprises an upstream core complex that mediates recruitment of two central players, FANCD2 and FANCI, to sites of stalled replication forks. Successful fork recovery depends on the Bloom's helicase BLM that participates in a larger protein complex ('BLMcx') containing topoisomerase III alpha, RMI1, RMI2 and replication protein A. We show that FANCD2 is an essential regulator of BLMcx functions: it maintains BLM protein stability and is crucial for complete BLMcx assembly; moreover, it recruits BLMcx to replicating chromatin during normal S-phase and mediates phosphorylation of BLMcx members in response to DNA damage. During replication stress, FANCD2 and BLM cooperate to promote restart of stalled replication forks while suppressing firing of new replication origins. In contrast, FANCI is dispensable for FANCD2-dependent BLMcx regulation, demonstrating functional separation of FANCD2 from FANCI.