范可尼贫血通路促进复制依赖性 DNA 链间交联修复。
The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.
机构信息
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Science. 2009 Dec 18;326(5960):1698-701. doi: 10.1126/science.1182372. Epub 2009 Nov 12.
Abstract
Fanconi anemia is a human cancer predisposition syndrome caused by mutations in 13 Fanc genes. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate DNA interstrand cross-links (ICLs). A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex, but how this complex confers ICL resistance remains enigmatic. Using a cell-free system, we showed that FANCI-FANCD2 is required for replication-coupled ICL repair in S phase. Removal of FANCD2 from extracts inhibits both nucleolytic incisions near the ICL and translesion DNA synthesis past the lesion. Reversal of these defects requires ubiquitylated FANCI-FANCD2. Our results show that multiple steps of the essential S-phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised.
摘要
范可尼贫血是一种由 13 个 FANC 基因的突变引起的人类癌症易感性综合征。该疾病的特征是基因组不稳定和细胞对产生 DNA 链间交联（ICLs）的化学物质的超敏感性。范可尼贫血途径激活的一个中心事件是 FANCI-FANCD2 复合物的单泛素化，但该复合物如何赋予 ICL 抗性仍然是个谜。我们使用无细胞系统表明，FANCI-FANCD2 是复制偶联的 ICL 在 S 期修复所必需的。从提取物中去除 FANCD2 会抑制 ICL 附近的核切割和损伤后跨损伤 DNA 合成。这些缺陷的逆转需要泛素化的 FANCI-FANCD2。我们的结果表明，当范可尼贫血途径受损时，必需的 S 期 ICL 修复机制的多个步骤都会失败。
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