RNA polymerase II drives FUS and EWSR1 exclusion from damaged chromatin

  • Cell Rep. 2026 Apr 8;45(4):117236. doi: 10.1016/j.celrep.2026.117236.
Sylvia Varhoshkova  1 ,  Christopher Chin Sang  2 ,  Liana Antonova  3 ,  Sonya Uzunova  3 ,  Dilyana Kirova  3 ,  Radoslav Aleksandrov  4 ,  Masato T Kanemaki  5 ,  Hyun O Lee  2 ,  Stoyno Stoynov  6
Affiliations
  • 1. Laboratory of Genomic Stability, Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. Bl.21, 1113 Sofia, Bulgaria. Electronic address: [email protected].
  • 2. Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 3. Laboratory of Genomic Stability, Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. Bl.21, 1113 Sofia, Bulgaria.
  • 4. Molecular Mechanisms of DNA Repair Laboratory, Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. Bl.21, 1113 Sofia, Bulgaria.
  • 5. Department of Chromosome Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Yata 1111, Mishima, Shizuoka 411-8540, Japan; Graduate Institute for Advanced Studies, SOKENDAI, Yata 1111, Mishima, Shizuoka 411-8540, Japan; Department of Biological Science, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 6. Laboratory of Genomic Stability, Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. Bl.21, 1113 Sofia, Bulgaria. Electronic address: [email protected].
PMID: 41955098 DOI: 10.1016/j.celrep.2026.117236
Abstract

FUS and EWSR1 are RNA-binding proteins that accumulate at DNA lesions in a poly(ADP-ribose)-dependent manner. Notably, upon foci formation, both proteins are gradually excluded from sites of complex DNA damage, yet the mechanism and significance of this exclusion remain unclear. Here, we show that inhibition of the transcription-associated cyclin-dependent kinases CDK7, CDK9, and CDK12/13, or degron-mediated depletion of RPB1, the catalytic subunit of RNA polymerase II, prevents the exclusion of FUS and EWSR1. RPB1 itself is also excluded from sites of DNA damage with kinetics similar to those of FUS. Furthermore, we demonstrate that CDK7 inhibition leads to reduced 53BP1 accumulation at DNA lesions in vivo. Our findings clarify a mechanism by which RPB1 and FUS/EWSR1 are excluded from damaged chromatin and highlight its importance in DNA repair coordination.

Keywords
53BP1; CDKs; CP: molecular biology; DNA repair; EWSR1; FET proteins; FUS; RNAPII; complex DNA lesions; exclusion; live-cell imaging.
Products