The SWI/SNF complex ATPase BRG1 prevented R-loop–associated transcription–replication conflicts.
Major Finding: The SWI/SNF complex ATPase BRG1 prevented R-loop–associated transcription–replication conflicts.
Concept: Aberrant R-loop accumulation can cause replication forks to stall, leading to DNA damage and cancer.
Impact: This work highlights the role of SWI/SNF complex–mediated chromatin remodeling in genome integrity.
Mutations affecting the mammalian SWI/SNF complex—particularly the main ATPase, BRG1 (also known as SMARCA4)—are common in many cancers. Bayona-Feliu and colleagues discovered a role for BRG1 in preventing genome-damaging transcription–replication (T-R) conflicts by preventing the excess accumulation of R-loops, which are structures consisting of a DNA–RNA hybrid along with single-stranded DNA displaced by the process of transcription. Consistent with this, depletion of BRG1 was associated with increased R-loop formation and buildup during S phase, causing replication forks to stall and ultimately leading to DNA damage and genomic instability. The accumulation of R-loops observed with BRG1 knockdown spanned the entire genome but was particularly prevalent in certain genomic areas, including regions of rDNA or subtelomeric DNA. Mechanistically, BRG1 appeared to help reduce R-loop–mediated T-R conflicts in concert with the Fanconi anemia pathway, which is involved in repairing DNA damage. Further investigation revealed that BRG1 colocalized with R-loop–dependent stalled replication forks, where it acted to modulate chromatin accessibility; specifically, BRG1 activity reduced chromatin accessibility at genomic regions that exhibited a large amount of R-loop accumulation and T-R conflicts upon BRG1 knockdown in the prior experiments. Additional evidence bolstered the notion that the mammalian SWI/SNF complex blocked R-loop–dependent DNA damage specifically through the BRG1 subunit, suggesting a role for BRG1 as a bona fide tumor suppressor. In summary, this work identifies a direct role for BRG1, commonly mutated in cancer, in protecting genome integrity; more broadly, this study illustrates the complex interplay between chromatin remodeling and the prevention of DNA damage.
Bayona-Feliu A, Barroso S, Muñoz S, Aguilera A. The SWI/SNF chromatin remodeling complex helps resolve R-loop-mediated transcription–replication conflicts. Nat Genet 2021 May 13 [Epub ahead of print].
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