Zhang Jieqiong, Dewar James M, Budzowska Magda, Motnenko Anna, Cohn Martin A, Walter Johannes C
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Biochemistry, University of Oxford, Oxford, UK.
Nat Struct Mol Biol. 2015 Mar;22(3):242-7. doi: 10.1038/nsmb.2956. Epub 2015 Feb 2.
DNA interstrand cross-links (ICLs) prevent strand separation during DNA replication and transcription and therefore are extremely cytotoxic. In metazoans, a major pathway of ICL repair is coupled to DNA replication, and it requires the Fanconi anemia pathway. In most current models, collision of a single DNA replication fork with an ICL is sufficient to initiate repair. In contrast, we show here that in Xenopus egg extracts two DNA replication forks must converge on an ICL to trigger repair. When only one fork reaches the ICL, the replicative CMG helicase fails to unload from the stalled fork, and repair is blocked. Arrival of a second fork, even when substantially delayed, rescues repair. We conclude that ICL repair requires a replication-induced X-shaped DNA structure surrounding the lesion, and we speculate on how this requirement helps maintain genomic stability in S phase.
DNA链间交联（ICLs）在DNA复制和转录过程中阻止链分离，因此具有极强的细胞毒性。在多细胞动物中，ICL修复的主要途径与DNA复制相关联，并且需要范可尼贫血途径。在当前大多数模型中，单个DNA复制叉与ICL的碰撞足以启动修复。相比之下，我们在此表明，在非洲爪蟾卵提取物中，两个DNA复制叉必须汇聚在一个ICL上才能触发修复。当只有一个叉到达ICL时，复制性CMG解旋酶无法从停滞的叉上卸载，修复被阻断。第二个叉的到达，即使大大延迟，也能挽救修复。我们得出结论，ICL修复需要围绕损伤形成一个由复制诱导的X形DNA结构，并且我们推测了这一要求如何有助于在S期维持基因组稳定性。
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