Armadillo Domain of ARID1A Directly Interacts with DNA-PKcs to Couple Chromatin Remodeling with Nonhomologous End Joining (NHEJ) Pathway

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.