Functional cross talk between the Fanconi anemia and ATRX/DAXX histone chaperone pathways promotes replication fork recovery
Functional cross talk between the Fanconi anemia and ATRX/DAXX histone chaperone pathways promotes replication fork recovery
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DOI：
10.1093/hmg/ddz250
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发表时间：
2020-04-01
影响因子：
3.5
通讯作者：
Sobeck, Alexandra
中科院分区：
文献类型：
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作者：
Raghunandan, Maya;Yeo, Jung Eun;Sobeck, Alexandra
范可尼贫血（FA）是一种染色体不稳定综合征，其特征是癌症易感性增加。具体来说，FA 途径的作用是在 DNA 复制过程中保护基因组稳定性。中央 FA 途径蛋白 FANCD2 定位于停滞的复制叉，并招募同源重组 (HR) 因子，例如 CtBP 相互作用蛋白 (CtIP)，以促进复制叉重新启动，同时抑制新起点激发。在这里，我们将 X 连锁α-地中海贫血迟缓综合征 (ATRX) 确定为 FANCD2 的新型物理和功能相互作用伙伴。 ATRX 是一种染色质重塑剂，可与死亡结构域相关蛋白 6 (DAXX) 形成复合物，将组蛋白变体 H3.3 沉积到特定的基因组区域。有趣的是，ATRX 最近与复制叉恢复有关；然而，其根本机制仍未完全了解。我们的研究结果表明，ATRX 与 FANCD2 形成组成型蛋白复合物，并保护 FANCD2 免遭蛋白酶体降解。 ATRX 和 FANCD2 定位于停滞的复制叉，在那里它们合作招募 CtIP 并促进 MRE11 核酸外切酶依赖性复制叉重新启动，同时抑制新复制起点的激发。值得注意的是，复制重新启动需要 ATRX/DAXX 和 FANCD2 协调一致的组蛋白 H3 伴侣活性，这表明协调的组蛋白 H3 变体沉积是复制 DNA 合成重新启动过程中的关键事件。最后，ATRX 还与 FANCD2 合作，促进直接诱导的 DNA 双链断裂的 HR 依赖性修复。我们认为 ATRX 是 FANCD2 的新型功能伙伴，可促进 S 期组蛋白沉积依赖性 HR 机制。
Fanconi anemia (FA) is a chromosome instability syndrome characterized by increased cancer predisposition. Specifically, the FA pathway functions to protect genome stability during DNA replication. The central FA pathway protein, FANCD2, locates to stalled replication forks and recruits homologous recombination (HR) factors such as CtBP interacting protein (CtIP) to promote replication fork restart while suppressing new origin firing. Here, we identify alpha-thalassemia retardation syndrome X-linked (ATRX) as a novel physical and functional interaction partner of FANCD2. ATRX is a chromatin remodeler that forms a complex with Death domain-associated protein 6 (DAXX) to deposit the histone variant H3.3 into specific genomic regions. Intriguingly, ATRX was recently implicated in replication fork recovery; however, the underlying mechanism(s) remained incompletely understood. Our findings demonstrate that ATRX forms a constitutive protein complex with FANCD2 and protects FANCD2 from proteasomal degradation. ATRX and FANCD2 localize to stalled replication forks where they cooperate to recruit CtIP and promote MRE11 exonuclease-dependent fork restart while suppressing the firing of new replication origins. Remarkably, replication restart requires the concerted histone H3 chaperone activities of ATRX/DAXX and FANCD2, demonstrating that coordinated histone H3 variant deposition is a crucial event during the reinitiation of replicative DNA synthesis. Lastly, ATRX also cooperates with FANCD2 to promote the HR-dependent repair of directly induced DNA double-stranded breaks. We propose that ATRX is a novel functional partner of FANCD2 to promote histone deposition-dependent HR mechanisms in S-phase.