ASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair

To recognize DNA adducts, nucleotide excision repair (NER) deploys the XPC sensor, which detects damage-induced helical distortions, followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place in chromatin where DNA is tightly wrapped aroun...

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Bibliographic Details
Published in:Nature communications 2023-07, Vol.14 (1), p.3892-3892, Article 3892
Main Authors: Maritz, Corina, Khaleghi, Reihaneh, Yancoskie, Michelle N., Diethelm, Sarah, Brülisauer, Sonja, Ferreira, Natalia Santos, Jiang, Yang, Sturla, Shana J., Naegeli, Hanspeter
Format: Article
Language:English
Subjects:
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14/1
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45/15
45/23
631/337/100/2285
631/337/1427/1430
631/337/458/1648
Adducts
Chromatin
Damage detection
Deoxyribonucleic acid
DNA
DNA adducts
DNA Repair
Genomes
Histone methyltransferase
Histones
Histones - genetics
Humanities and Social Sciences
Irradiation
Lesions
Methyltransferases
multidisciplinary
Nucleotide excision repair
Nucleotides
Priming
Repair
Science
Science (multidisciplinary)
Ultraviolet radiation
Verification
XPC protein
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Summary:To recognize DNA adducts, nucleotide excision repair (NER) deploys the XPC sensor, which detects damage-induced helical distortions, followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place in chromatin where DNA is tightly wrapped around histones. Here, we describe how the histone methyltransferase ASH1L, once activated by MRG15, helps XPC and TFIIH to navigate through chromatin and induce global-genome NER hotspots. Upon UV irradiation, ASH1L adds H3K4me3 all over the genome (except in active gene promoters), thus priming chromatin for XPC relocations from native to damaged DNA. The ASH1L-MRG15 complex further recruits the histone chaperone FACT to DNA lesions. In the absence of ASH1L, MRG15 or FACT, XPC is misplaced and persists on damaged DNA without being able to deliver the lesions to TFIIH. We conclude that ASH1L-MRG15 makes damage verifiable by the NER machinery through the sequential deposition of H3K4me3 and FACT. Due to the naturally dense packing of the genome, DNA repair factors encounter a topologically very intricate cellular context. We describe how the human ASH1L protein navigates excision repair factors to accelerate their search for DNA lesions.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-39635-7