Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: mechanistic insights.
Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: mechanistic insights.
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DOI：
10.1016/j.mrfmmm.2009.02.003
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发表时间：
2009-07-31
影响因子：
2.3
通讯作者：
Hinz, John M.
中科院分区：
文献类型：
--
作者：
Thompson, Larry H.;Hinz, John M.
关键词：
Fanconi贫血（FA）分子网络由15个“FANC”蛋白组成，其中13个与这种易患癌症的染色体不稳定性疾病患者的突变有关。尽管从历史上看，与FA突变相关的常见表型对DNA链间交联剂非常敏感，但文献支持ffc蛋白在应对复制聚合酶遇到的各种压力方面发挥更广泛的作用。我们试图将大量的观察结果整合到一个模型中，在这个模型中，fancm蛋白在DNA交联修复过程中协调以下生理事件：(a)激活fancm - atr依赖的s期检查点；(b)介导酶复制-叉断裂和交联解钩；(c)利用易出错的聚合酶通过翻译合成（TLS）填补由此产生的空白；(d)通过同源重组修复（HRR）修复产生的一端双链断裂。FANC核心亚配合物（FANCA， B， C， E， F， G， L, FAAP100）促进了交联和非交联损伤的TLS，如自发氧化碱损伤、UV-C光产物和烷基化碱。TLS可能有助于防止停滞的复制分叉断裂，从而保持染色体的连续性。不同的DNA损伤和复制抑制剂导致FANCD2-FANCI复合体被FANCM-FAAP24异二聚体转位酶募集到染色质上，核心亚复合体的FANCL泛素连接酶活性导致FANCD2-FANCI复合体的单泛素化。我们推测这种转位酶活性作为主要的损伤传感器，并帮助重塑被阻断的复制分叉，以促进检查点的激活和修复。促HRR需要FANCD2-FANCI的单泛素化，其中FANCD1/BRCA2和FANCN/PALB2蛋白在早期起作用。我们得出结论，对于非交联损伤和交联修复过程中分别发生的TLS和HRR事件，核心亚复合物都是必需的。FANCJ/BRIP1/BACH1解旋酶与BRCA1一起起作用，并可能去除复制的结构障碍，如鸟嘌呤四重结构，和/或协助交联解钩。
The Fanconi anemia (FA) molecular network consists of 15 “FANC” proteins, of which 13 are associated with mutations in patients with this cancer-prone chromosome instability disorder. Whereas historically the common phenotype associated with FA mutations is marked sensitivity to DNA interstrand crosslinking agents, the literature supports a more global role for FANC proteins in coping with diverse stresses encountered by replicative polymerases. We have attempted to reconcile and integrate numerous observations into a model in which FANC proteins coordinate the following physiological events during DNA crosslink repair: (a) activating a FANCM-ATR-dependent S-phase checkpoint; (b) mediating enzymatic replication-fork breakage and crosslink unhooking; (c) filling the resulting gap by translesion synthesis (TLS) by error-prone polymerase(s); and (d) restoring the resulting one-ended double-strand break by homologous recombination repair (HRR). The FANC core subcomplex (FANCA, B, C, E, F, G, L, FAAP100) promotes TLS for both crosslink and non-crosslink damage such as spontaneous oxidative base damage, UV-C photoproducts, and alkylated bases. TLS likely helps prevent stalled replication forks from breaking, thereby maintaining chromosome continuity. Diverse DNA damages and replication inhibitors result in monoubiquitination of the FANCD2-FANCI complex by the FANCL ubiquitin ligase activity of the core subcomplex upon its recruitment to chromatin by the FANCM-FAAP24 heterodimeric translocase. We speculate that this translocase activity acts as the primary damage sensor and helps remodel blocked replication forks to facilitate checkpoint activation and repair. Monoubiquitination of FANCD2-FANCI is needed for promoting HRR, in which the FANCD1/BRCA2 and FANCN/PALB2 proteins act at an early step. We conclude that the core subcomplex is required for both TLS and HRR occurring separately for non-crosslink damages and for both events during crosslink repair. The FANCJ/BRIP1/BACH1 helicase functions in association with BRCA1 and may remove structural barriers to replication, such as guanine quadruplex structures, and/or assist in crosslink unhooking.
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影响因子：
11.4
作者：
Abraham, J;Lemmers, B;Hakem, R
通讯作者：
Hakem, R
影响因子：
5.3
作者：
Akkari, YMN;Bateman, RL;Grompe, M
通讯作者：
Grompe, M
影响因子：
3.7
作者：
Centurion, SA;Kuo, HR;Lambert, WC
通讯作者：
Lambert, WC
影响因子：
4.7
作者：
BREDBERG, A;SANDOR, Z;BRANT, M
通讯作者：
BRANT, M
DOI：
10.1016/s0921-8777(99)00041-5
发表时间：
1999-09-13
期刊：
MUTATION RESEARCH-DNA REPAIR
影响因子：
--
作者：
Carreau, M;Alon, N;Buchwald, M
通讯作者：
Buchwald, M