Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
Nucleic Acids Res. 2013 Jul;41(13):6444-59. doi: 10.1093/nar/gkt348. Epub 2013 May 8.
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.
范可尼贫血症 (FA) 和布卢姆综合征具有重叠的表型，包括自发染色体异常和增加的癌症易感性。FA 蛋白途径包括一个上游核心复合物，该复合物介导两个中心参与者 FANCD2 和 FANCI 募集到停滞复制叉的位置。叉恢复的成功取决于布卢姆解旋酶 BLM，它参与了一个更大的蛋白质复合物（'BLMcx'），其中包含拓扑异构酶 III alpha、RMI1、RMI2 和复制蛋白 A。我们表明 FANCD2 是 BLMcx 功能的重要调节剂：它维持 BLM 蛋白稳定性，对于完整的 BLMcx 组装至关重要；此外，它在正常 S 期将 BLMcx 招募到复制染色质上，并介导 BLMcx 成员在 DNA 损伤后的磷酸化。在复制应激期间，FANCD2 和 BLM 合作促进停滞复制叉的重新启动，同时抑制新复制起点的点火。相比之下，FANCI 对于 FANCD2 依赖性 BLMcx 调节是可有可无的，这表明 FANCD2 与 FANCI 的功能分离。
