BRCA1-BARD1-catalyzed ubiquitination of histone H2A is an important regulator of the DNA damage response, priming chromatin for repair by homologous recombination. However, no specific deubiquitinating enzymes (DUBs) are known to antagonize this function. Here we identify ubiquitin specific protease-48 (USP48) as a H2A DUB, specific for the C-terminal BRCA1 ubiquitination site. Detailed biochemical analysis shows that an auxiliary ubiquitin, an additional ubiquitin that itself does not get cleaved, modulates USP48 activity, which has possible implications for its regulation in vivo. In cells we reveal that USP48 antagonizes BRCA1 E3 ligase function and in BRCA1-proficient cells loss of USP48 results in positioning 53BP1 further from the break site and in extended resection lengths. USP48 repression confers a survival benefit to cells treated with camptothecin and its activity acts to restrain gene conversion and mutagenic single-strand annealing. We propose that USP48 promotes genome stability by antagonizing BRCA1 E3 ligase function.

中文翻译：

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USP48 通过对 H2A 上的 BRCA1 泛素标记进行位点特异性切割来抑制切除。


BRCA1-BARD1 催化的组蛋白 H2A 泛素化是 DNA 损伤反应的重要调节因子，通过同源重组启动染色质修复。然而，目前还没有已知特定的去泛素化酶 (DUB) 可以拮抗这一功能。在这里，我们将泛素特异性蛋白酶 48 (USP48) 鉴定为 H2A DUB，对 C 端 BRCA1 泛素化位点具有特异性。详细的生化分析表明，辅助泛素（一种本身不会被切割的额外泛素）调节 USP48 活性，这可能对其体内调节产生影响。在细胞中，我们发现 USP48 拮抗 BRCA1 E3 连接酶功能，并且在 BRCA1 熟练的细胞中，USP48 的缺失导致 53BP1 距离断裂位点更远，并延长了切除长度。 USP48 抑制为用喜树碱处理的细胞带来了生存益处，其活性可抑制基因转换和诱变单链退火。我们认为 USP48 通过拮抗 BRCA1 E3 连接酶功能来促进基因组稳定性。