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首页> 外文期刊>Molecular and Cellular Biology >BRCA2 Is Ubiquitinated In Vivo and Interacts with USP11, a Deubiquitinating Enzyme That Exhibits Prosurvival Function in the Cellular Response to DNA Damage
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BRCA2 Is Ubiquitinated In Vivo and Interacts with USP11, a Deubiquitinating Enzyme That Exhibits Prosurvival Function in the Cellular Response to DNA Damage

机译：BRCA2是体内泛素化的，并与USP11（一种在细胞对DNA损伤的反应中表现出生存功能的去泛素化酶）相互作用

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摘要

Individuals carrying a germ line mutation of the breast cancer susceptibility gene BRCA2 are predisposed to breast, ovarian, and other types of cancer. The BRCA2 protein has been proposed to function in the repair of DNA double-strand breaks. Using an immunopurification-mass spectrometry approach to identify novel proteins that associate with the BRCA2 gene product, we found that a deubiquitinating enzyme, USP11, formed specific complexes with BRCA2. Moreover, BRCA2 was constitutively ubiquitinated in vivo in the absence of detectable proteasomal degradation. Mitomycin C (MMC) led to decreased BRCA2 protein levels associated with increased ubiquitination, consistent with proteasome-dependent degradation. While BRCA2 could be deubiquitinated by USP11 in transient overexpression assays, a catalytically inactive USP11 mutant had no effect on BRCA2 ubiquitination or protein levels. Antagonism of USP11 function either through expression of this mutant or through RNA interference increased cellular sensitivity to MMC in a BRCA2-dependent manner. All of these results imply that BRCA2 expression levels are regulated by ubiquitination in the cellular response to MMC-induced DNA damage and that USP11 participates in DNA damage repair functions within the BRCA2 pathway independently of BRCA2 deubiquitination.
机译：携带乳腺癌易感基因 BRCA2 的种系突变的个体易患乳腺癌，卵巢癌和其他类型的癌症。已经提出了BRCA2蛋白在DNA双链断裂的修复中起作用。使用免疫纯化-质谱法鉴定与BRCA2基因产物相关的新型蛋白质，我们发现去泛素化酶USP11与BRCA2形成了特定的复合物。此外，在没有可检测的蛋白酶体降解的情况下，BRCA2在体内组成型泛素化。丝裂霉素C（MMC）导致BRCA2蛋白水平降低，与泛素化增加相关，与蛋白酶体依赖性降解相一致。虽然在瞬时过表达测定中BRCA2可以被USP11去泛素化，但是催化失活的USP11突变体对BRCA2泛素化或蛋白质水平没有影响。 USP11的拮抗作用通过该突变体的表达或通过RNA干扰以BRCA2依赖性方式增加了对MMC的细胞敏感性。所有这些结果表明，BRCA2表达水平受细胞对MMC诱导的DNA损伤的响应中的泛素化调节，并且USP11参与BRCA2途径内的DNA损伤修复功能，而与BRCA2的去泛素作用无关。

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