Identification of a novel GR-ARID1a-P53BP1 protein complex involved in DNA damage repair and cell cycle regulation

作者：Felicity Stubbs, Benjamin P. Flynn, Caroline Rivers, Matthew T. Birnie, Andrew Herman, Erin E. Swinstead, Songjoon Baek, Hai Fang, Jillian Temple, Jason S. Carroll, Gordon L. Hager, Stafford L. Lightman, Becky Conway-Campbell · 发表于：Oncogene · 年份：2022 · DOI：10.1038/s41388-022-02516-2 · 被引用次数：13 · 研究领域：Chromatin Remodeling and Cancer、interferon and immune responses、Genomics and Chromatin Dynamics

ARID1a (BAF250), a component of human SWI/SNF chromatin remodeling complexes, is frequently mutated across numerous cancers, and its loss of function has been putatively linked to glucocorticoid resistance. Here, we interrogate the impact of siRNA knockdown of ARID1a compared to a functional interference approach in the HeLa human cervical cancer cell line. We report that ARID1a knockdown resulted in a significant global decrease in chromatin accessibility in ATAC-Seq analysis, as well as affecting a subset of genome-wide GR binding sites determined by analyzing GR ChIP-Seq data. Interestingly, the specific effects on gene expression were limited to a relatively small subset of glucocorticoid-regulated genes, notably those involved in cell cycle regulation and DNA repair. The vast majority of glucocorticoid-regulated genes were largely unaffected by ARID1a knockdown or functional interference, consistent with a more specific role for ARID1a in glucocorticoid function than previously speculated. Using liquid chromatography-mass spectrometry, we have identified a chromatin-associated protein complex comprising GR, ARID1a, and several DNA damage repair proteins including P53 binding protein 1 (P53BP1), Poly(ADP-Ribose) Polymerase 1 (PARP1), DNA damage-binding protein 1 (DDB1), DNA mismatch repair protein MSH6 and splicing factor proline and glutamine-rich protein (SFPQ), as well as the histone acetyltransferase KAT7, an epigenetic regulator of steroid-dependent transcription, DN...