Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress.
Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress.
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DOI：
10.1038/s41467-023-36933-y
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发表时间：
2023-03-11
影响因子：
16.6
通讯作者：
Schlacher, Katharina
中科院分区：
文献类型：
--
作者：
Tomaszowski, Karl-Heinz;Roy, Sunetra;Guerrero, Carolina;Shukla, Poojan;Keshvani, Caezaan;Chen, Yue;Ott, Martina;Wu, Xiaogang;Zhang, Jianhua;DiNardo, Courtney D.;Schindler, Detlev;Schlacher, Katharina
原型癌症易感性疾病范可尼贫血（FA）通过23个FANC基因中的任何一个的双等位基因突变来鉴定。令人困惑的是，在小鼠中单独失活一个Fanc基因，在没有额外的外部压力的情况下，无法忠实地模拟人类多效性疾病。在这里，我们发现FA患者经常显示FANC共突变。在小鼠中组合示例性纯合亚型Brca 2/Fancd 1和Rad 51 c/Fanco突变，表型模仿人FA，具有骨髓衰竭、癌症快速死亡、细胞癌症-药物超敏反应和严重复制不稳定性。这些严重的表型与在具有单基因功能失活的小鼠中观察到的不显著的表型形成对比，揭示了Fanc突变之间的意想不到的协同作用。除了FA，乳腺癌基因组分析证实多基因FANC肿瘤突变与较低的生存率相关，扩展了我们对FANC基因的理解，超越了上位性FA途径。总的来说，这些数据建立了一个多基因复制应激概念作为一个可测试的原则，其中共同出现的一个独特的第二个基因突变放大和驱动内源性复制应激，基因组不稳定性和疾病。Tomaszowski等人表明，Brca 2和Rad 51 c的共突变协同驱动癌症和发育疾病，这是出乎意料的，因为它们的上位DNA修复作用，并扩展了我们对其肿瘤抑制功能的理解。
The prototypic cancer-predisposition disease Fanconi Anemia (FA) is identified by biallelic mutations in any one of twenty-three FANC genes. Puzzlingly, inactivation of one Fanc gene alone in mice fails to faithfully model the pleiotropic human disease without additional external stress. Here we find that FA patients frequently display FANC co-mutations. Combining exemplary homozygous hypomorphic Brca2/Fancd1 and Rad51c/Fanco mutations in mice phenocopies human FA with bone marrow failure, rapid death by cancer, cellular cancer-drug hypersensitivity and severe replication instability. These grave phenotypes contrast the unremarkable phenotypes seen in mice with single gene-function inactivation, revealing an unexpected synergism between Fanc mutations. Beyond FA, breast cancer-genome analysis confirms that polygenic FANC tumor-mutations correlate with lower survival, expanding our understanding of FANC genes beyond an epistatic FA-pathway. Collectively, the data establish a polygenic replication stress concept as a testable principle, whereby co-occurrence of a distinct second gene mutation amplifies and drives endogenous replication stress, genome instability and disease. Tomaszowski et al show that co-mutations in Brca2 and Rad51c synergistically drive cancer and developmental disease, which was unexpected given their epistatic DNA repair roles, and expands our understanding of their tumor suppressive functions.
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
4.3
作者：
Bakker ST;de Winter JP;te Riele H
通讯作者：
te Riele H
DOI：
10.1093/jnci/djw302
发表时间：
2017-07-01
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Kuchenbaecker KB;McGuffog L;Barrowdale D;Lee A;Soucy P;Dennis J;Domchek SM;Robson M;Spurdle AB;Ramus SJ;Mavaddat N;Terry MB;Neuhausen SL;Schmutzler RK;Simard J;Pharoah PDP;Offit K;Couch FJ;Chenevix-Trench G;Easton DF;Antoniou AC
通讯作者：
Antoniou AC
DOI：
10.1016/0167-8817(85)90031-8
发表时间：
1985-01-01
期刊：
MUTATION RESEARCH
影响因子：
--
作者：
LAMBERT, WC;LAMBERT, MW
通讯作者：
LAMBERT, MW