ARID1A regulates R-loop associated DNA replication stress

Stirling, P.; Tsai, S.; Chang, E. Y.-C.; Fournier, L.-A.; Wells, J. P.; Minaker, S. W.; Zhu, Y. D.; Wang, A. Y.-H.; Wang, Y.; Huntsman, D. G.

doi:10.1101/2020.11.16.384446

bioRxiv · 10.1101/2020.11.16.384446

ARID1A regulates R-loop associated DNA replication stress

Stirling, P.·Tsai, S.·Chang, E. Y.-C.·Fournier, L.-A.·Wells, J. P.·Minaker, S. W.·Zhu, Y. D.·Wang, A. Y.-H.·Wang, Y.·Huntsman, D. G.

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Abstract

ARID1A is lost in up to 7% of all cancers, and this frequency 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 remodeller 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.

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Stirling, P., Tsai, S., Chang, E. Y.-C., Fournier, L.-A., Wells, J. P., Minaker, S. W., Zhu, Y. D., Wang, A. Y.-H., Wang, Y., Huntsman, D. G.. 2020-11-16. ARID1A regulates R-loop associated DNA replication stress. https://doi.org/10.1101/2020.11.16.384446

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