The deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors
The deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors
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去泛素化酶 USP15 调节同源重组修复和癌细胞对 PARP 抑制剂的反应
DOI：
10.1038/s41467-019-09232-8
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发表时间：
2019-03-15
影响因子：
16.6
通讯作者：
Pei, Huadong
中科院分区：
文献类型：
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作者：
Peng, Yihan;Liao, Qingchao;Pei, Huadong
聚(ADP-核糖)聚合酶抑制剂(PARPI)选择性地杀伤BRCA1/2突变引起的同源重组缺陷的乳腺癌和卵巢癌。也有临床证据表明，PARPI在没有BRCA突变的乳腺癌和卵巢癌中有效，但其潜在机制尚不清楚。在这里，我们报告了去泛素化酶USP15通过调节HR来影响癌细胞对PARPI的反应。从机制上讲，USP15被MDC1招募到DNA双链断裂(DSB)，这需要MDC1的FHA结构域和USP15的磷酸化Ser678。随后，USP15去泛素化BARD1BRCT结构域，促进BARD1HP1γ相互作用，导致BRCA1/BARD1DSB滞留。USP15基因敲除小鼠在体内表现出基因组的不稳定性。此外，与癌症相关的USP15突变，随着USP15-BARD1相互作用的减少，增加了癌细胞中PARP抑制剂的敏感性。因此，我们的结果确定了一种新的HR调节因子，它是使用PARP抑制剂治疗癌症的潜在生物标记物。
Poly-(ADP-ribose) polymerase inhibitors (PARPi) selectively kill breast and ovarian cancers with defects in homologous recombination (HR) caused by BRCA1/2 mutations. There is also clinical evidence for the utility of PARPi in breast and ovarian cancers without BRCA mutations, but the underlying mechanism is not clear. Here, we report that the deubiquitylating enzyme USP15 affects cancer cell response to PARPi by regulating HR. Mechanistically, USP15 is recruited to DNA double-strand breaks (DSBs) by MDC1, which requires the FHA domain of MDC1 and phosphorylated Ser678 of USP15. Subsequently, USP15 deubiquitinates BARD1 BRCT domain, and promotes BARD1-HP1γ interaction, resulting in BRCA1/BARD1 retention at DSBs. USP15 knockout mice exhibit genomic instability in vivo. Furthermore, cancer-associated USP15 mutations, with decreased USP15-BARD1 interaction, increases PARP inhibitor sensitivity in cancer cells. Thus, our results identify a novel regulator of HR, which is a potential biomarker for therapeutic treatment using PARP inhibitors in cancers.