Deficiency in mammalian histone H2B ubiquitin ligase Bre1 (Rnf20/Rnf40) leads to replication stress and chromosomal instability.
Deficiency in mammalian histone H2B ubiquitin ligase Bre1 (Rnf20/Rnf40) leads to replication stress and chromosomal instability.
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DOI：
10.1158/0008-5472.can-11-2209
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发表时间：
2012-04-15
期刊：
影响因子：
11.2
通讯作者：
Brown JM
中科院分区：
文献类型：
--
作者：
Chernikova SB;Razorenova OV;Higgins JP;Sishc BJ;Nicolau M;Dorth JA;Chernikova DA;Kwok S;Brooks JD;Bailey SM;Game JC;Brown JM
哺乳动物Bre 1复合物（人的Bre 1 A/B（RNF 20/40）和小鼠的Bre 1 a/B（Rnf 20/40））与其酵母同系物Bre 1在组蛋白H2 B的单泛素化中作为泛素连接酶起类似作用。这种泛素化促进了组蛋白H3在K4和K79的甲基化，并解释了Bre 1及其同源物在转录调控中的作用。其他人最近的研究表明，Bre 1作为一种肿瘤抑制因子，增加选择的肿瘤抑制基因的表达和抑制选择的癌基因。在这项研究中，我们提出了一个额外的机制，通过维持基因组的稳定性，肿瘤抑制Bre 1。我们跟踪Bre 1缺陷细胞中基因组不稳定性的演变，从复制相关的双链断裂（DSB）到特定的基因组重排，解释了DNA含量的快速增加并触发断裂-融合-桥循环。我们发现，异常的RNA-DNA结构（R-环）构成了一个重要的来源DSB在Bre 1缺陷细胞。结合先前报道的同源重组缺陷，R-环的产生可能是Bre 1缺陷细胞中复制应激和基因组不稳定性的引发剂。我们认为Bre 1缺陷引发的基因组不稳定性可能是获得侵袭性表型之前的重要早期步骤，因为我们发现在睾丸腺瘤和原位癌的癌前病变中BRE 1 A/B和二甲基化H3 K79水平降低。
Mammalian Bre1 complexes (BRE1A/B (RNF20/40) in humans and Bre1a/b (Rnf20/40) in mice) function similarly to their yeast homolog Bre1 as ubiquitin ligases in monoubiquitination of histone H2B. This ubiquitination facilitates methylation of histone H3 at K4 and K79, and accounts for the roles of Bre1 and its homologs in transcriptional regulation. Recent studies by others suggested that Bre1 acts as a tumor suppressor, augmenting expression of select tumor suppressor genes and suppressing select oncogenes. In this study we present an additional mechanism of tumor suppression by Bre1 through maintenance of genomic stability. We track the evolution of genomic instability in Bre1-deficient cells from replication-associated double-strand breaks (DSBs) to specific genomic rearrangements that explain a rapid increase in DNA content and trigger breakage-fusion-bridge cycles. We show that aberrant RNA-DNA structures (R-loops) constitute a significant source of DSBs in Bre1-deficient cells. Combined with a previously reported defect in homologous recombination, generation of R-loops is a likely initiator of replication stress and genomic instability in Bre1-deficient cells. We propose that genomic instability triggered by Bre1 deficiency may be an important early step that precedes acquisition of an invasive phenotype, as we find decreased levels of BRE1A/B and dimethylated H3K79 in testicular seminoma and in the premalignant lesion in situ carcinoma.