TY - JOUR
T1 - Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability
AU - Geijer, Marit E.
AU - Zhou, Di
AU - Selvam, Kathiresan
AU - Steurer, Barbara
AU - Mukherjee, Chirantani
AU - Evers, Bastiaan
AU - Cugusi, Simona
AU - van Toorn, Marvin
AU - van der Woude, Melanie
AU - Janssens, Roel C.
AU - Kok, Yannick P.
AU - Gong, Wenzhi
AU - Raams, Anja
AU - Lo, Calvin S.Y.
AU - Lebbink, Joyce H.G.
AU - Geverts, Bart
AU - Plummer, Dalton A.
AU - Bezstarosti, Karel
AU - Theil, Arjan F.
AU - Mitter, Richard
AU - Houtsmuller, Adriaan B.
AU - Vermeulen, Wim
AU - Demmers, Jeroen A.A.
AU - Li, Shisheng
AU - van Vugt, Marcel A.T.M.
AU - Lans, Hannes
AU - Bernards, René
AU - Svejstrup, Jesper Q.
AU - Ray Chaudhuri, Arnab
AU - Wyrick, John J.
AU - Marteijn, Jurgen A.
N1 - Funding Information:
We thank the Optical Imaging Center and the Proteomics Center of the Erasmus Medical Center for support with microscopes and mass spectrometry analysis. We thank the Advanced Sequencing Facility of the Francis Crick Institute for technical assistance with DRB/TTchem-seq. We acknowledge infrastructural support from the Josephine Nefkens Precision Cancer Treatment Program. This work is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society and was funded by a grant from the Dutch Cancer Society (KWF grant 10506). This work was further funded by the Dutch organization for Scientific Research (NWO-ALW), which awarded a VIDI (864.13.004) and VICI (VI.C.182.025) grant to J.A.M. A.R.C. is supported by the Dutch Cancer Society (KWF grant 11008) and NWO VIDI (193.131). S.L. is funded by the National Science Foundation (MCB-1615550). J.J.W. is funded by the National Institute of Environmental Health Sciences (grants R01ES028698, R21ES029655 and R21ES029302). M.A.T.M.v.V. is funded by a grant from the European Research Council (ERC CoS grant 682421). H.L. is funded by The Netherlands Organization for Scientific Research (project number 711.018.007) and Cancergenomics.nl. W.V. was funded by a grant from the European Research Council (agreement 340988). J.Q.S. was supported by the Francis Crick Institute (which receives funding from Cancer Research UK (FC001166), the UK Medical Research Council (FC001166) and the Wellcome Trust (FC001166)) and by a grant from the European Research Council (agreement 693327).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/6/9
Y1 - 2021/6/9
N2 - Correct transcription is crucial for life. However, DNA damage severely impedes elongating RNA polymerase II, causing transcription inhibition and transcription-replication conflicts. Cells are equipped with intricate mechanisms to counteract the severe consequence of these transcription-blocking lesions. However, the exact mechanism and factors involved remain largely unknown. Here, using a genome-wide CRISPR–Cas9 screen, we identified the elongation factor ELOF1 as an important factor in the transcription stress response following DNA damage. We show that ELOF1 has an evolutionarily conserved role in transcription-coupled nucleotide excision repair (TC-NER), where it promotes recruitment of the TC-NER factors UVSSA and TFIIH to efficiently repair transcription-blocking lesions and resume transcription. Additionally, ELOF1 modulates transcription to protect cells against transcription-mediated replication stress, thereby preserving genome stability. Thus, ELOF1 protects the transcription machinery from DNA damage via two distinct mechanisms.
AB - Correct transcription is crucial for life. However, DNA damage severely impedes elongating RNA polymerase II, causing transcription inhibition and transcription-replication conflicts. Cells are equipped with intricate mechanisms to counteract the severe consequence of these transcription-blocking lesions. However, the exact mechanism and factors involved remain largely unknown. Here, using a genome-wide CRISPR–Cas9 screen, we identified the elongation factor ELOF1 as an important factor in the transcription stress response following DNA damage. We show that ELOF1 has an evolutionarily conserved role in transcription-coupled nucleotide excision repair (TC-NER), where it promotes recruitment of the TC-NER factors UVSSA and TFIIH to efficiently repair transcription-blocking lesions and resume transcription. Additionally, ELOF1 modulates transcription to protect cells against transcription-mediated replication stress, thereby preserving genome stability. Thus, ELOF1 protects the transcription machinery from DNA damage via two distinct mechanisms.
UR - http://www.scopus.com/inward/record.url?scp=85107487420&partnerID=8YFLogxK
U2 - 10.1038/s41556-021-00692-z
DO - 10.1038/s41556-021-00692-z
M3 - Article
C2 - 34108662
AN - SCOPUS:85107487420
VL - 23
SP - 608
EP - 619
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 6
ER -