Abstract
The stable association between SOSS and INTAC maintains genome stability by limiting R-loop accumulation.
Major Finding: The stable association between SOSS and INTAC maintains genome stability by limiting R-loop accumulation.
Concept: R-loop accumulation is suppressed by SSB1 intrinsically disordered region–mediated SOSS–INTAC condensate formation.
Impact: These results reveal a mechanism of genome stability maintenance that can be disrupted during oncogenesis.
Genome integrity is maintained, in part, through proper transcription regulation, but R-loop formation during transcription promotes replication stress and genome instability due to exposed single-stranded DNA (ssDNA). However, the mechanisms that underlie R-loop regulation during transcription and their contribution to genome instability are not fully understood. Xu, Li, Chen, Xiong, and colleagues sought to evaluate these mechanisms using immunoprecipitation followed by mass spectrometry and identified the formation of a stable complex between the genome stability regulator SOSS and the transcription regulator INTAC. This SOSS–INTAC complex was observed to bind at both active promoters and enhancers and was recruited to ssDNA by SSB1, a subunit of the SOSS–INTAC complex that potently binds to ssDNA. RNA polymerase II (Pol II) pausing was also found to be regulated by SOSS–INTAC, allowing for control of promoter-proximal termination and chromatin accessibility at promoter regions. R-loop accumulation can occur at promoters harboring high Pol II levels, and evaluation of whether R-loops alter the recruitment of SOSS–INTAC to chromatin demonstrated that R-loops are recognized by the SSB1 subunit and lead to increased SOSS–INTAC at these promoters. Moreover, the SOSS–INTAC complex was shown to reciprocally attenuate R-loop levels through its endonuclease activity, thereby regulating genome stability. Further investigation into other biochemical features of SOSS–INTAC revealed that the SSB1 subunit can form liquid-like condensates and drive the condensation of SOSS–INTAC through its intrinsically disordered region (IDR), and potential cancer hotspot mutations in the SSB1 IDR, especially in arginine within the C-terminal IDR, impair the condensation capacity of SOSS–INTAC. Additionally, depletion of SSB1 induces the accumulation of R-loops at SOSS–INTAC-bound promoters, while SSB1 condensate formation suppresses R-loop levels at SOSS–INTAC targets. In conclusion, this study shows that the stable association between SOSS and INTAC limits transcription-associated R-loops to maintain genome stability and suggests that cancer-associated mutations that disrupt SOSS–INTAC condensation could compromise genome stability and contribute to oncogenic programs.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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