ASH1L histone methyltransferase regulates the handoff between damage recognition factors in global-genome nucleotide excision repair.
- Balbo Pogliano C Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, 8057, Zurich, Switzerland.
- Gatti M Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
- Rüthemann P Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, 8057, Zurich, Switzerland.
- Garajovà Z Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, 8057, Zurich, Switzerland.
- Penengo L Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
- Naegeli H Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, 8057, Zurich, Switzerland. naegelih@vetpharm.uzh.ch.
- 2017-11-08
Published in:
- Nature communications. - 2017
Cell Line
DNA Damage
DNA Repair
DNA-Binding Proteins
HeLa Cells
Histone-Lysine N-Methyltransferase
Histones
Humans
Methylation
Nucleosomes
Protein Interaction Domains and Motifs
Pyrimidine Dimers
RNA, Small Interfering
Skin Neoplasms
Transcription Factors
Ultraviolet Rays
English
Global-genome nucleotide excision repair (GG-NER) prevents ultraviolet (UV) light-induced skin cancer by removing mutagenic cyclobutane pyrimidine dimers (CPDs). These lesions are formed abundantly on DNA wrapped around histone octamers in nucleosomes, but a specialized damage sensor known as DDB2 ensures that they are accessed by the XPC initiator of GG-NER activity. We report that DDB2 promotes CPD excision by recruiting the histone methyltransferase ASH1L, which methylates lysine 4 of histone H3. In turn, methylated H3 facilitates the docking of the XPC complex to nucleosomal histone octamers. Consequently, DDB2, ASH1L and XPC proteins co-localize transiently on histone H3-methylated nucleosomes of UV-exposed cells. In the absence of ASH1L, the chromatin binding of XPC is impaired and its ability to recruit downstream GG-NER effectors diminished. Also, ASH1L depletion suppresses CPD excision and confers UV hypersensitivity. These findings show that ASH1L configures chromatin for the effective handoff between damage recognition factors during GG-NER activity.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.1038/s41467-017-01080-8
- PMID 29109511
- Persistent URL
- https://sonar.ch/global/documents/47392
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