聚(ADP核糖)聚合酶1(PARP1)对几种类型的癌症的进展至关重要。然而，PARP1在三阴乳腺癌(TNBC)中如何稳定以促进基因组稳定尚不清楚。我们在这里展示了脱泛素化酶USP15与PARP1相互作用并脱去其泛素化，以促进其稳定性，从而刺激DNA修复、基因组稳定和TNBC细胞增殖。在患有乳腺癌的个体中发现的两种PARP1突变体(E90K和S104R)增强了PARP1-USP15相互作用并抑制了PARP1的泛素化，从而提高了PARP1的蛋白水平。重要的是，我们发现雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2(HER2)通过不同机制抑制了USP15介导的PARP1稳定。ER结合到USP15启动子上抑制其表达，PR抑制USP15的脱泛素化活性，HER2取消了PARP1-USP15相互作用。在TNBC中这三种受体的特定缺失导致高水平的PARP1，从而增加了碱基切除修复和女性TNBC细胞的生存。© 2023.作者授予Springer Nature America，Inc.独家许可。

Poly(ADP-ribose) polymerase 1 (PARP1) is essential for the progression of several types of cancers. However, whether and how PARP1 is stabilized to promote genomic stability in triple-negative breast cancer (TNBC) remains unknown. Here, we demonstrated that the deubiquitinase USP15 interacts with and deubiquitinates PARP1 to promote its stability, thereby stimulating DNA repair, genomic stability and TNBC cell proliferation. Two PARP1 mutations found in individuals with breast cancer (E90K and S104R) enhanced the PARP1-USP15 interaction and suppressed PARP1 ubiquitination, thereby elevating the protein level of PARP1. Importantly, we found that estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) inhibited USP15-mediated PARP1 stabilization through different mechanisms. ER bound to the USP15 promoter to suppress its expression, PR suppressed the deubiquitinase activity of USP15, and HER2 abrogated the PARP1-USP15 interaction. The specific absence of these three receptors in TNBC results in high PARP1 levels, leading to increases in base excision repair and female TNBC cell survival.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.