ARID1A regulates chromatin organization and establishment of epigenetic marks for DSB repair and transcription silencing

ABSTRACT: AT-rich interactive domain-containing protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. ARID1A contributes to DNA damage response pathways, and we previously reported that ARID1A loss is associated with mutational signatures linked to DNA repair defects. Here we show that ARID1A is promoting both DNA double-strand breaks (DSBs) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). ARID1A is accumulated at DSBs after DNA damage and regulates the chromatin loop formation at DSB sites by interacting with the cohesin subunit RAD21 and CTCF insulator protein promoting their enrichment around the DSBs. Further analysis demonstrates that ARID1A’s involvement in DSB repair is accompanied by alterations of chromatin accessibility and distribution of activating histone marks at DSBs. ARID1A binds to and promotes the recruitment of the HDAC1 to control transcription repression at these DSBs. Altogether, ARID1A simultaneously regulates DSB repair and transcription silencing in transcriptionally active chromatin. ARID1A depletion resulted in defective DSB repair, which subsequently led to accumulation of micronuclei, activation of cGAS-STING pathway and an increased expression of immunomodulatory cytokines and chemokines upon IR treatment. Furthermore, low ARID1A expression in cancer patients receiving radiotherapy was associated with higher infiltration of several immune cells. The high mutation rate of ARID1A in various cancer types highlights its clinical relevance as a promising biomarker that correlates with the level of immune regulatory cytokines and can estimate the levels of tumor-infiltrating immune cells and response to combination of radio- and immunotherapy.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Gianluca Sigismondo  

LAB HEAD: Peter Schmezer1

PROVIDER: PXD047225 | Pride | 2024-06-22

REPOSITORIES: Pride