How Fanconi anemia proteins promote the four Rs: replication, recombination, repair, and recovery.
How Fanconi anemia proteins promote the four Rs: replication, recombination, repair, and recovery.
复制标题
范可尼贫血蛋白如何促进 4 个 R：复制、重组、修复和恢复。
DOI：
10.1002/em.20109
复制
发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Jones,NigelJ
中科院分区：
文献类型：
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作者：
Thompson,LarryH;Hinz,JohnM;Yamada,NAlice;Jones,NigelJ
遗传复杂疾病范可尼贫血（FA）包括癌症易感性、发育缺陷和由于细胞凋亡增加导致的骨髓衰竭。FA细胞表型包括对DNA交联损伤的普遍敏感性、氧化应激症状和X-连锁HPRT基因的突变性降低。在这篇综述文章中，我们提出了一个新的启发式分子模型，可容纳这些不同的功能FA细胞。在我们看来，FANCA、-C和-G蛋白质，既存在于细胞质中，也存在于细胞核中，具有整合的双重作用，它们感知并将细胞质氧化应激的信息传递给细胞核，在细胞核中它们参与核核心复合物的进一步组装和功能（NCCFA= FANCA/B/C/E/F/G/L）。反过来，NCCFA通过执行FANCD 2的关键单泛素化，在碱基损伤和链断裂的位点促进DNA复制，这一事件在某种程度上有助于稳定阻断和断裂的复制叉。这种稳定促进了两种过程：在阻塞病变部位的经病变合成（例如，氧化性碱基损伤），其通过易错聚合酶产生点突变，以及同源重组介导的断裂叉的重新启动，其自发产生并且当交联被ERCC 1-XPF内切核酸酶解钩时。在缺乏关键的FANCD 2单泛素化步骤的情况下，断裂的复制叉通过塌陷成更难以通过重组重新启动的构型并且易于通过非同源末端连接进行异常修复而进一步失去染色单体连续性。因此，FA调节途径通过监测氧化应激和有效应对DNA复制过程中伴随的氧化DNA损伤来促进染色体完整性。Environ.摩尔诱变剂，2005. 2005年出版Wiley利斯公司
The genetically complex disease Fanconi anemia (FA) comprises cancer predisposition, developmental defects, and bone marrow failure due to elevated apoptosis. The FA cellular phenotype includes universal sensitivity to DNA crosslinking damage, symptoms of oxidative stress, and reduced mutability at the X‐linkedHPRTgene. In this review article, we present a new heuristic molecular model that accommodates these varied features of FA cells. In our view, the FANCA, ‐C, and ‐G proteins, which are both cytoplasmic and nuclear, have an integrated dual role in which they sense and convey information about cytoplasmic oxidative stress to the nucleus, where they participate in the further assembly and functionality of the nuclear core complex (NCCFA= FANCA/B/C/E/F/G/L). In turn, NCCFAfacilitates DNA replication at sites of base damage and strand breaks by performing the critical monoubiquitination of FANCD2, an event that somehow helps stabilize blocked and broken replication forks. This stabilization facilitates two kinds of processes: translesion synthesis at sites of blocking lesions (e.g., oxidative base damage), which produces point mutations by error‐prone polymerases, and homologous recombination‐mediated restart of broken forks, which arise spontaneously and when crosslinks are unhooked by the ERCC1‐XPF endonuclease. In the absence of the critical FANCD2 monoubiquitination step, broken replication forks further lose chromatid continuity by collapsing into a configuration that is more difficult to restart through recombination and prone to aberrant repair through nonhomologous end joining. Thus, the FA regulatory pathway promotes chromosome integrity by monitoring oxidative stress and coping efficiently with the accompanying oxidative DNA damage during DNA replication. Environ. Mol. Mutagen., 2005. Published 2005 Wiley‐Liss, Inc.