ARID1A regulates R-loop associated DNA replication stress


Autoři: Shuhe Tsai aff001;  Louis-Alexandre Fournier aff001;  Emily Yun-chia Chang aff001;  James P. Wells aff001;  Sean W. Minaker aff001;  Yi Dan Zhu aff001;  Alan Ying-Hsu Wang aff001;  Yemin Wang aff002;  David G. Huntsman aff002;  Peter C. Stirling aff001
Působiště autorů: Terry Fox Laboratory, BC Cancer, Vancouver, Canada aff001;  Department of Molecular Oncology, BC Cancer, Vancouver, Canada aff002;  Department of Medical Genetics, University of British Columbia, Vancouver, Canada aff003
Vyšlo v časopise: ARID1A regulates R-loop associated DNA replication stress. PLoS Genet 17(4): e1009238. doi:10.1371/journal.pgen.1009238
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009238

Souhrn

ARID1A is a core DNA-binding subunit of the BAF chromatin remodeling complex, and is lost in up to 7% of all cancers. The frequency of ARID1A loss increases in certain cancer types, such as clear cell ovarian carcinoma where ARID1A protein is lost in about 50% of cases. While the impact of ARID1A loss on the function of the BAF chromatin remodeling complexes is likely to drive oncogenic gene expression programs in specific contexts, ARID1A also binds genome stability regulators such as ATR and TOP2. Here we show that ARID1A loss leads to DNA replication stress associated with R-loops and transcription-replication conflicts in human cells. These effects correlate with altered transcription and replication dynamics in ARID1A knockout cells and to reduced TOP2A binding at R-loop sites. Together this work extends mechanisms of replication stress in ARID1A deficient cells with implications for targeting ARID1A deficient cancers.

Klíčová slova:

Cell staining – DNA damage – DNA replication – DNA transcription – Genomics – Chromatin – Immunoprecipitation – Small interfering RNA


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