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RNA polymerase II drives FUS and EWSR1 exclusion from damaged chromatin

Sylvia Varhoshkova1, Christopher Chin Sang2, Liana Antonova1

  • 1Laboratory of Genomic Stability, Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. Bl.21, 1113 Sofia, Bulgaria.

Cell Reports
|April 9, 2026
PubMed

Insights

RNA-binding proteins FUS and EWSR1 are excluded from DNA damage sites. Inhibiting transcription kinases or depleting RNA polymerase II prevents this exclusion, clarifying DNA repair mechanisms.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • FUS and EWSR1 are RNA-binding proteins known to accumulate at DNA lesions.
  • The mechanism and significance of their exclusion from complex DNA damage sites are not well understood.

Purpose of the Study:

  • To elucidate the mechanism behind the exclusion of FUS and EWSR1 from DNA damage sites.
  • To investigate the role of transcription-associated kinases and RNA polymerase II in this process.

Main Methods:

  • Inhibition of transcription-associated cyclin-dependent kinases (CDK7, CDK9, CDK12/13).
  • Degron-mediated depletion of RNA polymerase II (RPB1).
  • Observation of FUS, EWSR1, and RPB1 localization at DNA damage sites.

Main Results:

  • Inhibition of CDKs or depletion of RPB1 prevented FUS and EWSR1 exclusion from DNA damage sites.
  • RPB1 itself showed similar exclusion kinetics to FUS.
  • CDK7 inhibition reduced 53BP1 accumulation at DNA lesions in vivo.

Conclusions:

  • RPB1 and FUS/EWSR1 exclusion from damaged chromatin is dependent on transcription activity.
  • This exclusion mechanism is important for coordinating DNA repair processes.
Keywords:
53BP1CDKsCP: molecular biologyDNA repairEWSR1FET proteinsFUSRNAPIIcomplex DNA lesionsexclusionlive-cell imaging

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