Genomic instability, defective spermatogenesis, immunodeficiency, and cancer in a mouse model of the RIDDLE syndrome.
Genomic instability, defective spermatogenesis, immunodeficiency, and cancer in a mouse model of the RIDDLE syndrome.
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DOI：
10.1371/journal.pgen.1001381
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发表时间：
2011-04
期刊：
影响因子：
4.5
通讯作者：
Hakem R
中科院分区：
文献类型：
--
作者：
Bohgaki T;Bohgaki M;Cardoso R;Panier S;Zeegers D;Li L;Stewart GS;Sanchez O;Hande MP;Durocher D;Hakem A;Hakem R
真核细胞已经进化到使用复杂的DNA损伤信号传导和修复途径来维持基因组的完整性。RNF 168是一种新型的E3连接酶，在ATM、γ-H2 A. X、MDC 1和RNF 8的下游起作用。它已被证明泛素化组蛋白H2 A，并促进其他DNA损伤反应蛋白，包括53 BP 1，DNA断裂的网站招聘。此外，RNF 168突变与人类RIDDLE综合征有因果关系。在这项研究中，我们报告说，Rnf 168 −/−小鼠免疫缺陷，并表现出增加的放射敏感性。rnf 168 −/−男性的精子发生受损与年龄有关。有趣的是，与H2a.x−/−、Mdc 1 −/−和Rnf 8 −/−细胞相反，在Rnf 168 −/−细胞中，53 bp 1对DNA双链断裂的瞬时募集被消除。值得注意的是，类似于53 bp 1失活，但不同于H2a.x缺陷，Rnf 168的失活损害了胸腺细胞中的长距离V（D）J重组，并导致B细胞类别转换连接处的长插入。Rnf 168的缺失增加了基因组的不稳定性，并与p53失活协同促进肿瘤发生。我们的数据揭示了Rnf 168的重要生理功能，并支持其在DNA双链断裂的γ-H2 a. x-Mdc 1-Rnf 8依赖性和非依赖性信号通路中的作用。这些结果突出了RNF 168在DNA断裂信号传导的分层网络中的核心作用，该网络维持基因组完整性并抑制哺乳动物的癌症发展。DNA损伤的修复是基本的，如许多人类综合征、免疫缺陷和与DNA损伤信号传导和修复缺陷相关的癌症所示。RIDDLE综合征是由人RNF 168基因突变引起的一种新型遗传性疾病，临床上以放射敏感性、免疫缺陷、畸形和学习困难为特征。RNF 168是一种E3连接酶，在DNA断裂位点修饰组蛋白和染色质结构。在这项研究中，我们表明，Rnf 168缺乏小鼠导致放射敏感性增加，免疫缺陷和精子发生缺陷。此外，Rnf 168和p53的双重失活导致癌症风险增加。总的来说，这些数据证明了Rnf 168的重要和广泛的生理功能。
Eukaryotic cells have evolved to use complex pathways for DNA damage signaling and repair to maintain genomic integrity. RNF168 is a novel E3 ligase that functions downstream of ATM,γ-H2A.X, MDC1, and RNF8. It has been shown to ubiquitylate histone H2A and to facilitate the recruitment of other DNA damage response proteins, including 53BP1, to sites of DNA break. In addition, RNF168 mutations have been causally linked to the human RIDDLE syndrome. In this study, we report that Rnf168−/− mice are immunodeficient and exhibit increased radiosensitivity. Rnf168−/− males suffer from impaired spermatogenesis in an age-dependent manner. Interestingly, in contrast to H2a.x−/−, Mdc1−/−, and Rnf8−/− cells, transient recruitment of 53bp1 to DNA double-strand breaks was abolished in Rnf168−/− cells. Remarkably, similar to 53bp1 inactivation, but different from H2a.x deficiency, inactivation of Rnf168 impairs long-range V(D)J recombination in thymocytes and results in long insertions at the class-switch junctions of B-cells. Loss of Rnf168 increases genomic instability and synergizes with p53 inactivation in promoting tumorigenesis. Our data reveal the important physiological functions of Rnf168 and support its role in both γ-H2a.x-Mdc1-Rnf8-dependent and -independent signaling pathways of DNA double-strand breaks. These results highlight a central role for RNF168 in the hierarchical network of DNA break signaling that maintains genomic integrity and suppresses cancer development in mammals. The repair of DNA damage is fundamental as illustrated by the many human syndromes, immunodeficiencies, and cancers associated with defects in DNA damage signaling and repair. RIDDLE syndrome, caused by mutations of the human RNF168, is a novel hereditary disease clinically characterized by radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties. RNF168 is an E3 ligase that modifies histones and chromatin structure at sites of DNA breaks. In this study, we show that Rnf168 deficiency in mice leads to increased radiosensitivity, immunodeficiency, and defective spermatogenesis. Additionally, dual inactivation of Rnf168 and p53 leads to increased cancer risk. Collectively these data demonstrate important and broad physiological functions for Rnf168.
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影响因子：
56.9
作者：
Celeste, A;Petersen, S;Nussenzweig, A
通讯作者：
Nussenzweig, A
DOI：
10.1083/jcb.200510130
发表时间：
2006-04-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bekker-Jensen S;Lukas C;Kitagawa R;Melander F;Kastan MB;Bartek J;Lukas J
通讯作者：
Lukas J
影响因子：
64.5
作者：
Bassing, CH;Suh, H;Alt, FW
通讯作者：
Alt, FW
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
RAD18 传递 DNA 损伤信号以引发同源重组修复。
影响因子：
21.3
作者：
Huang, Jun;Huen, Michael S. Y.;Kim, Hongtae;Leung, Charles Chung Yun;Glover, J. N. Mark;Yu, Xiaochun;Chen, Junjie
通讯作者：
Chen, Junjie