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Structural basis of human transcription-DNA repair coupling.
- Source :
-
Nature [Nature] 2021 Oct; Vol. 598 (7880), pp. 368-372. Date of Electronic Publication: 2021 Sep 15. - Publication Year :
- 2021
-
Abstract
- Transcription-coupled DNA repair removes bulky DNA lesions from the genome <superscript>1,2</superscript> and protects cells against ultraviolet (UV) irradiation <superscript>3</superscript> . Transcription-coupled DNA repair begins when RNA polymerase II (Pol II) stalls at a DNA lesion and recruits the Cockayne syndrome protein CSB, the E3 ubiquitin ligase, CRL4 <superscript>CSA</superscript> and UV-stimulated scaffold protein A (UVSSA) <superscript>3</superscript> . Here we provide five high-resolution structures of Pol II transcription complexes containing human transcription-coupled DNA repair factors and the elongation factors PAF1 complex (PAF) and SPT6. Together with biochemical and published <superscript>3,4</superscript> data, the structures provide a model for transcription-repair coupling. Stalling of Pol II at a DNA lesion triggers replacement of the elongation factor DSIF by CSB, which binds to PAF and moves upstream DNA to SPT6. The resulting elongation complex, EC <superscript>TCR</superscript> , uses the CSA-stimulated translocase activity of CSB to pull on upstream DNA and push Pol II forward. If the lesion cannot be bypassed, CRL4 <superscript>CSA</superscript> spans over the Pol II clamp and ubiquitylates the RPB1 residue K1268, enabling recruitment of TFIIH to UVSSA and DNA repair. Conformational changes in CRL4 <superscript>CSA</superscript> lead to ubiquitylation of CSB and to release of transcription-coupled DNA repair factors before transcription may continue over repaired DNA.<br /> (© 2021. The Author(s).)
- Subjects :
- Carrier Proteins chemistry
Carrier Proteins metabolism
Carrier Proteins ultrastructure
DNA Helicases chemistry
DNA Helicases metabolism
DNA Helicases ultrastructure
DNA Repair Enzymes chemistry
DNA Repair Enzymes metabolism
DNA Repair Enzymes ultrastructure
DNA-Binding Proteins chemistry
DNA-Binding Proteins metabolism
DNA-Binding Proteins ultrastructure
Humans
Models, Molecular
Multiprotein Complexes metabolism
Poly-ADP-Ribose Binding Proteins chemistry
Poly-ADP-Ribose Binding Proteins metabolism
Poly-ADP-Ribose Binding Proteins ultrastructure
RNA Polymerase II metabolism
Transcription Elongation, Genetic
Transcription Factor TFIIH chemistry
Transcription Factor TFIIH metabolism
Transcription Factor TFIIH ultrastructure
Transcription Factors chemistry
Transcription Factors metabolism
Transcription Factors ultrastructure
Ubiquitin-Protein Ligases chemistry
Ubiquitin-Protein Ligases metabolism
Ubiquitin-Protein Ligases ultrastructure
Ubiquitination
Cryoelectron Microscopy
DNA Repair
Multiprotein Complexes chemistry
Multiprotein Complexes ultrastructure
RNA Polymerase II chemistry
RNA Polymerase II ultrastructure
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 598
- Issue :
- 7880
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 34526721
- Full Text :
- https://doi.org/10.1038/s41586-021-03906-4