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- Title
ARID1A regulates R-loop associated DNA replication stress.
- Authors
Tsai, Shuhe; Fournier, Louis-Alexandre; Chang, Emily Yun-chia; Wells, James P.; Minaker, Sean W.; Zhu, Yi Dan; Wang, Alan Ying-Hsu; Wang, Yemin; Huntsman, David G.; Stirling, Peter C.
- Abstract
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. Author summary: DNA is an incredibly busy molecule. It is bound by an ever-changing array of proteins, which control how our cells read the instructions encoded within DNA, through a process called transcription. DNA also must be replicated, condensed, and segregated every time a cell divides. These processes of DNA replicating and transcribing must not interfere with one another or the cell risks damage to DNA and potentially changes to the DNA code called mutations. In cancer many DNA transactions are perturbed, and this has been associated with damaging collisions between replication and transcription. Here we find that a gene called ARID1A, which is frequently lost in cancer cells, prevents such collisions between replication and transcription machinery. Loss of ARID1A has many effects on the cell, but in this context it seems to change the location and activity of an important regulator of DNA twisting and untangling called Topoisomerase 2A. Understanding how loss of ARID1A creates stresses on dividing cancer cells provides new opportunities to develop or apply therapies that could exploit this stress.
- Subjects
PAPHOS (Cyprus); DNA replication; DNA topoisomerase I; RENAL cell carcinoma; GENES; DNA damage; PROTEIN microarrays
- Publication
PLoS Genetics, 2021, Vol 17, Issue 4, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1009238