Kanno Shin-Ichiro, Kobayashi Takayasu, Watanabe Reiko, Kurimasa Akihiro, Tanaka Kozo, Yasui Akira, Ui Ayako
Division of Dynamic Proteome in Cancer and Aging, Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi 980-8575, Japan.
Center for Animal and Gene Research, Tohoku University, Sendai, Miyagi 980-8575, Japan.
Nucleic Acids Res. 2025 Feb 27;53(5). doi: 10.1093/nar/gkaf150.
The SWI/SNF chromatin-remodeling complex that comprises multiple subunits orchestrates diverse cellular processes, including gene expression, DNA repair, and DNA replication, by sliding and releasing nucleosomes. AT-interacting domain-rich protein 1A (ARID1A) and ARID1B (ARID1A/B), a pivotal subunit, have significant relevance in cancer management because they are frequently mutated in a broad range of cancer types. To delineate the protein network involving ARID1A/B, we investigated the interactions of this with other proteins under physiological conditions. The ARID domain of ARID1A/B interacts with proteins involved in transcription and DNA/RNA metabolism. Several proteins are responsible for genome integrity maintenance, including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), bound to the armadillo (ARM) domain of ARID1A/B. Introducing a knock-in mutation at the binding amino acid of DNA-PKcs in HCT116 cells reduced the autophosphorylation of DNA-PKcs and the recruitment of LIG4 in response to ionizing radiation. Our findings suggest that within the SWI/SNF complex, ARID1A couples DNA double-strand break repair processes with chromatin remodeling via the ARM domains to directly engage with DNA-PKcs to maintain genome stability.
由多个亚基组成的SWI/SNF染色质重塑复合体通过滑动和释放核小体来协调多种细胞过程，包括基因表达、DNA修复和DNA复制。富含AT相互作用结构域的蛋白1A（ARID1A）和ARID1B（ARID1A/B）作为关键亚基，在癌症治疗中具有重要意义，因为它们在多种癌症类型中经常发生突变。为了描绘涉及ARID1A/B的蛋白质网络，我们研究了其在生理条件下与其他蛋白质的相互作用。ARID1A/B的ARID结构域与参与转录和DNA/RNA代谢的蛋白质相互作用。几种蛋白质负责维持基因组完整性，包括与ARID1A/B的犰狳（ARM）结构域结合的DNA依赖性蛋白激酶催化亚基（DNA-PKcs）。在HCT116细胞中，在DNA-PKcs的结合氨基酸处引入敲入突变，可降低DNA-PKcs的自磷酸化以及响应电离辐射时LIG4的募集。我们的研究结果表明，在SWI/SNF复合体中，ARID1A通过ARM结构域将DNA双链断裂修复过程与染色质重塑相结合，直接与DNA-PKcs相互作用以维持基因组稳定性。
