文章：

追踪brca和范可尼贫血蛋白的连接网络

Tracing the network connecting brca and fanconi anaemia proteins

原文发布日期：2004-04-01

DOI: 10.1038/nrc1321

类型: Review Article

开放获取: 否

要点：

1. Inherited mutations that affect a single allele of either BRCA1 or BRCA2 cause a hereditary breast and ovarian cancer syndrome, which accounts for 30–60% of familial breast cancer cases.
2. Biallelic germline mutations in BRCA2 are also associated with the very rare D1 complementation group of Fanconi anaemia. The clinical features of FA-D1 patients — who develop Wilms' tumour, breast cancer and medulloblastoma — differ from typical FA cases.
3. BRCA and FA proteins work in a network of connected biological processes, and not in a linear sequence of events that constitutes a single 'pathway'. One key purpose of the network is to deal with lesions that block DNA replication — such as intra- or inter-strand DNA crosslinks — so preserving chromosome stability during the S and G2 phases of the cell cycle.
4. When sensed, replication-blocking lesions trigger cell-cycle arrest, which requires DNA-damage-activated checkpoint kinases such as ATM (which is mutated in ataxia telangiectasia) or ATR (which is mutated in Seckel syndrome), as well as BRCA1 and the FA protein FANCD2.
5. Replication-blocking lesions can be repaired — and replication resumed — through error-free processes that involve homologous recombination or error-prone, mutagenic processes that involve translesion synthesis. BRCA2 and RAD51 work directly to mediate recombination, as might FANCD2, whereas the precise functions of other FA proteins in recombination or translesion synthesis are unclear at present.
6. Each of the BRCA and FA proteins is likely to have very distinct functions within this network of biological processes. So, the clinical syndromes — including cancers — that are associated with their inactivation could be more mechanistically distinct than is supposed at present, demanding careful consideration of how emerging molecular understanding can best be translated to improve patient care.

要点翻译：

1. 影响BRCA1或BRCA2单个等位基因的遗传性突变会引起遗传性乳腺癌-卵巢癌综合征，该综合征占家族性乳腺癌病例的30%-60%。
2. BRCA2的双等位基因种系突变也与极罕见的范可尼贫血D1互补群相关。FA-D1患者（会发展为肾母细胞瘤、乳腺癌和髓母细胞瘤）的临床特征与典型FA病例不同。
3. BRCA和FA蛋白在一个相互关联的生物过程网络中发挥作用，而非构成单一“通路”的线性事件序列。该网络的一个关键功能是处理阻碍DNA复制的损伤（如链内或链间DNA交联），从而在细胞周期的S期和G2期维持染色体稳定性。
4. 当被感知时，复制阻断损伤会触发细胞周期停滞，这需要DNA损伤激活的检查点激酶（如共济失调毛细血管扩张症中突变的ATM，或塞克尔综合征中突变的ATR）以及BRCA1和FA蛋白FANCD2的参与。
5. 复制阻断损伤可通过无错误修复过程（如同源重组）或易错突变过程（如跨损伤合成）进行修复并恢复复制。BRCA2和RAD51直接介导重组，FANCD2可能也具有类似功能，而其他FA蛋白在重组或跨损伤合成中的具体功能目前尚不明确。
6. 每种BRCA和FA蛋白在这一生物过程网络中可能都具有独特功能。因此，与其失活相关的临床综合征（包括癌症）在机制上的差异性可能远超当前认知，这要求我们慎重考虑如何将新兴的分子生物学知识最佳地转化为改善患者诊疗的策略。

英文摘要：

Recent evidence connects the proteins that are encoded by the BRCA1 and BRCA2 breast cancer susceptibility genes, and other tumour suppressors — such as the Fanconi anaemia gene products — to cell-cycle checkpoint control and DNA repair by homologous recombination. Do these connections represent a linear biological pathway or do they, instead, reflect a network of processes that prevent aberrations in chromosome structure during the S and G2 phases of the cell cycle? This distinction has important implications for current models to explain the pathogenesis of the cancer susceptibility syndromes that are associated with BRCA or Fanconi anaemia gene mutations.

摘要翻译： 

最新证据表明，由乳腺癌易感基因BRCA1和BRCA2编码的蛋白质，以及其他肿瘤抑制因子（如范可尼贫血相关基因产物），与细胞周期检查点调控及同源重组介导的DNA修复密切相关。这些关联究竟代表一条线性生物学通路，还是反映了在细胞周期S期和G2期防止染色体结构异常的一系列网络过程？这一区分对于解释与BRCA或范可尼贫血基因突变相关的癌症易感综合征发病机制模型具有重要意义。

原文链接：

Tracing the network connecting brca and fanconi anaemia proteins