细胞周期检查点激酶1（Checkpoint kinase 1，CHK1）是细胞对DNA损伤的应答的关键效应分子，是所有细胞周期检查点的重要组成部分。最近的报告显示，CHK1在临床设置中高度表达于多种癌症类型中。然而，肿瘤细胞中CHK1表达调控的机制仍不清楚。本文报道了溴结构域含有蛋白7（BRD7）对CHK1的负性调控作用。具体而言，BRD7沉默通过p53非依赖的方式在多种肿瘤细胞系中提高了CHK1（但不是CHK2）的mRNA和蛋白水平。此外，BRD7沉默通过减少CHK1的泛素化来稳定CHK1。机制上，BRD7敲除不仅增加了CHK1的脱泛素化酶USP1的水平，还促进了CHK1和USP1的相互作用，从而增强了CHK1的脱泛素化作用。USP1敲除消除了BRD7沉默诱导的CHK1表达上调。在生物学上，BRD7沉默引起的CHK1在肿瘤细胞中的高表达通过增强肿瘤细胞凋亡作用，显著增加了细胞对CHK1抑制剂的敏感性。而同时敲除CHK1或USP1则逆转了这种效应。综上所述，我们的研究结果表明BRD7可能是一个潜在的基因或药物靶点，可提升联合治疗中针对CHK1的化疗药物的疗效。© 2023年。细胞死亡分化协会（ADMC）。

Checkpoint kinase 1 (CHK1), a key effector in the cellular response to DNA lesions, is a crucial component of all cell cycle checkpoints. Recent reports have revealed that CHK1 is highly expressed in numerous cancer types in the clinical settings. However, the mechanisms underlying the regulation of CHK1 expression in tumor cells remain unclear. Here, we report that CHK1 is negatively regulated by the bromodomain-containing protein 7 (BRD7). Specifically, BRD7 silencing increased CHK1 (but not CHK2) expression at both mRNA and protein levels, in a p53-independent manner in multiple tumor cell lines. Furthermore, BRD7 silencing stabilized CHK1 via reducing its ubiquitination. Mechanistically, BRD7 knockdown not only increased the levels of USP1, a deubiquitinase for CHK1, but also promoted the interaction between CHK1 and USP1, subsequently enhancing the de-ubiquitination of CHK1. USP1 knockdown abrogated BRD7 silencing-induced CHK1 induction. Biologically, the increased expression of CHK1 in tumor cells caused by BRD7 silencing significantly increased cell sensitivity to CHK1 inhibitors by enhancing tumor cell apoptosis, and this effect was reversed by the simultaneous knockdown of CHK1 or USP1. Taken together, our findings suggest that BRD7 is a potential genetic or drug target that may help to improve the efficacy of chemotherapeutic drugs targeting CHK1 in combinatorial therapy.© 2023. Cell Death Differentiation Association (ADMC).