UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors
UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors
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DOI：
10.1016/j.cell.2018.11.024
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发表时间：
2019-01-24
期刊：
影响因子：
64.5
通讯作者：
Shiloh, Yosef
中科院分区：
文献类型：
--
作者：
Jachimowicz, Ron D.;Beleggia, Filippo;Shiloh, Yosef
基因组不稳定性可能是人类遗传疾病和癌症的标志。我们确定了一个有害的UBQLN4突变的常染色体隐性遗传综合征的家庭让人想起基因组不稳定性疾病。UBQLN4缺陷导致对遗传毒性应激的敏感性增加和DNA双链断裂（DSB）修复延迟。蛋白酶体穿梭因子UBQLN 4被ATM磷酸化，并与泛素化的MRE 11相互作用，介导同源重组介导的DSB修复（HRR）的早期步骤。UBQLN 4的缺失导致MRE 11的染色质保留，促进体外和体内的非生理性HRR活性。相反，UBQLN4过表达抑制HRR并有利于非同源末端连接。此外，我们发现UBQLN 4在侵袭性肿瘤中过表达。与这些肿瘤中的HRR缺陷一致，UBQLN 4过表达与PARP1抑制剂敏感性相关。因此，UBQLN 4通过从受损的染色质中去除MRE 11来减少HRR活性，从而为UBQLN 4过表达肿瘤中的PARP 1抑制剂治疗提供了治疗窗口。
Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic windowfor PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.