Figure 3.

ARID1A is involved in DDR through different mechanisms. ARID1A is implicated on both HR and NHEJ. On DNA double-strand breaks (DSB), ATR directly interacts and recruits ARID1A containing SWI/SNF complex, which serves to (i) reduce nucleosome density at the DSB and facilitate DNA end resection to create single-strand for RPA deposition. The RPA-covered single-strand DNA is necessary for RAD51-mediated homology search and strand invasion (116). (ii) In addition, ARID1A is necessary for ATR activation, which, through CHK1, signals G₂-M arrest (117). (iii) In NHEJ, SWI/SNF complex is necessary for recruitment of Ku70/80 and XRCC4 at DSB. Thus, loss of ARID1A leads to reduced NHEJ activity (118). (iv) ARID1A transcriptionally represses the mitosis driver kinase AURKA. In cells with ARID1A loss, AURKA-PLK1-CDC25C pathway is upregulated. In addition, CDC25C activity is negatively regulated by ARID1A–ATR–CHK pathway under DNA damage conditions, thereby strictly controlling the CDC25 activity in ARID1A WT cells. CDC25C activity is hence de-repressed in ARID1A mutated cells, leading to weakened G2-M checkpoint (119). (v) In addition, SWI/SNF complex may recruit TOP2A to chromatin, which, through ATR and other mechanisms, may signal S and G2-M arrest. These factors might render tumor cells sensitive to small-molecule ATR inhibitors as these agents impair the ability of cells to mount adequate DDRs while at the same time accelerating mitotic entry (120).