The splicing factor XAB2 interacts with ERCC1-XPF and XPG for R-loop processing

Evi Goulielmaki, Maria Tsekrekou, Nikos Batsiotos, Mariana Ascensão-Ferreira, Eleftheria Ledaki, Kalliopi Stratigi, Georgia Chatzinikolaou, Pantelis Topalis, Theodore Kosteas, Janine Altmüller, Jeroen A. Demmers, Nuno L. Barbosa-Morais and George A. Garinis ()
Additional contact information
Evi Goulielmaki: Foundation for Research and Technology-Hellas
Maria Tsekrekou: Foundation for Research and Technology-Hellas
Nikos Batsiotos: Foundation for Research and Technology-Hellas
Mariana Ascensão-Ferreira: Faculdade de Medicina da Universidade de Lisboa, Avenida Professor Egas Moniz
Eleftheria Ledaki: Foundation for Research and Technology-Hellas
Kalliopi Stratigi: Foundation for Research and Technology-Hellas
Georgia Chatzinikolaou: Foundation for Research and Technology-Hellas
Pantelis Topalis: Foundation for Research and Technology-Hellas
Theodore Kosteas: Foundation for Research and Technology-Hellas
Janine Altmüller: University of Cologne
Jeroen A. Demmers: Erasmus University Medical Center
Nuno L. Barbosa-Morais: Faculdade de Medicina da Universidade de Lisboa, Avenida Professor Egas Moniz
George A. Garinis: Foundation for Research and Technology-Hellas

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract RNA splicing, transcription and the DNA damage response are intriguingly linked in mammals but the underlying mechanisms remain poorly understood. Using an in vivo biotinylation tagging approach in mice, we show that the splicing factor XAB2 interacts with the core spliceosome and that it binds to spliceosomal U4 and U6 snRNAs and pre-mRNAs in developing livers. XAB2 depletion leads to aberrant intron retention, R-loop formation and DNA damage in cells. Studies in illudin S-treated cells and Csbm/m developing livers reveal that transcription-blocking DNA lesions trigger the release of XAB2 from all RNA targets tested. Immunoprecipitation studies reveal that XAB2 interacts with ERCC1-XPF and XPG endonucleases outside nucleotide excision repair and that the trimeric protein complex binds RNA:DNA hybrids under conditions that favor the formation of R-loops. Thus, XAB2 functionally links the spliceosomal response to DNA damage with R-loop processing with important ramifications for transcription-coupled DNA repair disorders.

Date: 2021
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DOI: 10.1038/s41467-021-23505-1

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