2. Academic Validation
  3. The phosphorylated trimeric SOSS1 complex and RNA polymerase II trigger liquid-liquid phase separation at double-strand breaks

The phosphorylated trimeric SOSS1 complex and RNA polymerase II trigger liquid-liquid phase separation at double-strand breaks

  • Cell Rep. 2023 Dec 26;42(12):113489. doi: 10.1016/j.celrep.2023.113489.
Qilin Long 1,  Marek Sebesta 2,  Katerina Sedova 3,  Vojtech Haluza 3,  Adele Alagia 1,  Zhichao Liu 1,  Richard Stefl 4,  Monika Gullerova 5
Affiliations

Affiliations

  • 1 Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
  • 2 Central European Institute of Technology (CEITEC), Masaryk University, 62500 Brno, Czech Republic. Electronic address: [email protected].
  • 3 Central European Institute of Technology (CEITEC), Masaryk University, 62500 Brno, Czech Republic.
  • 4 Central European Institute of Technology (CEITEC), Masaryk University, 62500 Brno, Czech Republic; National Center for Biomolecular Research, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic.
  • 5 Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. Electronic address: [email protected].
PMID: 38039132 DOI: 10.1016/j.celrep.2023.113489
Abstract

Double-strand breaks (DSBs) are the most severe type of DNA damage. Previously, we demonstrated that RNA polymerase II (RNAPII) phosphorylated at the tyrosine 1 (Y1P) residue of its C-terminal domain (CTD) generates RNAs at DSBs. However, the regulation of transcription at DSBs remains enigmatic. Here, we show that the damage-activated tyrosine kinase c-Abl phosphorylates hSSB1, enabling its interaction with Y1P RNAPII at DSBs. Furthermore, the trimeric SOSS1 complex, consisting of hSSB1, INTS3, and c9orf80, binds to Y1P RNAPII in response to DNA damage in an R-loop-dependent manner. Specifically, hSSB1, as a part of the trimeric SOSS1 complex, exhibits a strong affinity for R-loops, even in the presence of replication protein A (RPA). Our in vitro and in vivo data reveal that the SOSS1 complex and RNAPII form dynamic liquid-like repair compartments at DSBs. Depletion of the SOSS1 complex impairs DNA repair, underscoring its biological role in the R-loop-dependent DNA damage response.

Keywords

CP: Molecular biology; DNA damage; DNA:RNA hybrids; LLPS; R-loops; RNA polymerase II; SOSS1 complex; c-Abl kinase; hSSB1; phase-separation; phosphorylation.

Figures