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ASH1L methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair [ChIP-Seq ASH1L-CTD]

ABSTRACT: To recognize DNA damage, nucleotide excision repair (NER) deploys a multipart mechanism by which the XPC sensor detects helical distortions followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place on chromatin where DNA is wrapped around histones. We show that the histone methyltransferase ASH1L, once activated by MRG15, accelerates global-genome NER activity. Upon UV irradiation, ASH1L deposits H3K4me3 marks all over the genome (except in gene promoters), thus priming chromatin for relocations of XPC from native to damaged DNA. ASH1L further recruits the histone chaperone FACT to UV lesions. In the absence of ASH1L, MRG15 or FACT, XPC persists on damaged DNA without being able to deliver lesions to the TFIIH verifier. We conclude that ASH1L implements repair hotspots whose H3K4me3 and FACT occupancy confers an active promoter-like code and organization of histones that make DNA damage verifiable by the NER machinery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227008 | GEO | 2023/06/08

REPOSITORIES: GEO

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ASH1L methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair [ATAC-Seq]

Project description:To recognize DNA damage, nucleotide excision repair (NER) deploys a multipart mechanism by which the XPC sensor detects helical distortions followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place on chromatin where DNA is wrapped around histones. We show that the histone methyltransferase ASH1L, once activated by MRG15, accelerates global-genome NER activity. Upon UV irradiation, ASH1L deposits H3K4me3 marks all over the genome (except in gene promoters), thus priming chromatin for relocations of XPC from native to damaged DNA. ASH1L further recruits the histone chaperone FACT to UV lesions. In the absence of ASH1L, MRG15 or FACT, XPC persists on damaged DNA without being able to deliver lesions to the TFIIH verifier. We conclude that ASH1L implements repair hotspots whose H3K4me3 and FACT occupancy confers an active promoter-like code and organization of histones that make DNA damage verifiable by the NER machinery.

2023-06-08 | GSE227007 | GEO

ASH1L methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair [ChIP-Seq]

2023-06-08 | GSE214182 | GEO

Whole genome expression data from formalin-fixed parrafin embedded (FFPE) primary and metastatic melanomas

Project description:The dominant genetic signature found in melanoma is C to T mutations due to UV radiation. Nucleotide excision repair (NER) recognises and repairs UV-induced DNA damage. We aimed to determine the effect of high UV exposure on the melanoma transcriptome and key NER transcripts in melanoma tumours in association with clinical and genetic features of the disease. 196 primary or metastatic melanomas were utilised for this study. Solar elastosis and transcriptome data was collected. mRNA transcript levels of NER components XPC, DDB1 and DDB2 were quantified and compared to clinical parameters. Solar elastosis negatively correlated with Breslow thickness (-0.251, p=0.017) and was significantly lower in BRAFV600E melanomas. Lower XPC expression was associated with BRAFV600E and NRASQ61R mutations, earlier age of diagnosis and poorer survival. Transcriptome profiling identified an over-representation of DNA repair processes in high vs low solar elastosis. Further analysis revealed DNA repair and kinase activity related transcripts in the low XPC melanomas. XPC deficiency is associated with the presence of kinase mutations and an aggressive disease phenotype, both of which result from the hypermutability of melanoma.

2016-12-31 | GSE59455 | GEO

Structural basis of TFIIH activation for nucleotide excision repair

Project description:Nucleotide excision repair (NER) is the major DNA repair pathway that removes UV-induced and bulky DNA lesions. There is currently no structure of NER intermediates, which form around the large multisubunit transcription factor IIH (TFIIH). Here we report the cryo-EM structure of an NER intermediate containing TFIIH and the NER factor XPA. Compared to its transcription conformation, the TFIIH structure is rearranged such that its ATPase subunits XPB and XPD bind double- and single-stranded DNA, consistent with their translocase and helicase activities, respectively. XPA releases the inhibitory kinase module of TFIIH, displaces a ‘plug’ element from the DNA-binding pore in XPD, and together with the NER factor XPG stimulates XPD activity. Our results explain how TFIIH is switched from a transcription to a repair factor, and provide the basis for a mechanistic analysis of the NER pathway.

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Structure of TFIIK for phosphorylation of CTD of RNA polymerase II

Project description:TFIIH is a 10-protein complex that is conserved through out eukaryotes. TFIIH has two primary cellular functions: transcription initiation and nucleotide excision repair (NER). In transcription initiation, TFIIH acts as a structural scaffold, phosphorylates the RNA polymerase II (pol II) C-terminal domain (CTD) and translocates promoter DNA through the pol II active site to facilitate start site selection. In NER, again is a structural scaffold, opens a bubble around damaged DNA and scans the damaged strand for bulky lesions. In yeast (Saccharomyces cerevisiae), TFIIH is composed of the two helicases Ssl2 and Rad3, the scaffolding subunits Tfb1, Tfb2, Tfb4 and Ssl1 and the kinase subunits Kin28, Ccl1 and Tfb3.

2021-07-07 | PXD021211 | Pride

Structure of TFIIH/Rad4-Rad23-Rad33 in damaged DNA opening in Nucleotide Excision Repair

Project description:TFIIH is a 10-protein complex that is conserved throughout eukaryotes. TFIIH has two primary cellular functions: transcription initiation and nucleotide excision repair (NER). NER in eukaryotes begins by recognition of a bulky lesion by the obligate dimer Rad4-Rad23. This is followed closely by the recruitment of TFIIH which is a structural scaffold, opens a bubble around damaged DNA and scans the damaged strand for bulky lesions. This facilitates the recruitment of two exonucleases which excise the damages strand before an undamaged complement is synthesize. In yeast (Saccharomyces cerevisiae), TFIIH is composed of the two helicases Ssl2 and Rad3, the scaffolding subunits Tfb1, Tfb2, Tfb4 and Ssl1 and the kinase subunits Kin28, Ccl1 and Tfb3, though these later 3 are dispensable for NER.

2021-07-07 | PXD021212 | Pride

ASH1L guards cis-regulatory elements against cyclobutane pyrimidine dimer induction

Project description:The histone methyltransferase ASH1L, first discovered for its role in transcription, has been shown to accelerate the removal of ultraviolet (UV) light-induced cyclobutane pyrimidine dimers (CPDs) by nucleotide excision repair. Previous reports demonstrated that CPD excision is most efficient at transcriptional regulatory elements, including enhancers, relative to other genomic sites. Therefore, we analyzed DNA damage maps in ASH1L-proficient and ASH1L-deficient cells to understand how ASH1L controls enhancer stability. This comparison showed that ASH1L protects enhancer sequences against the induction of CPDs besides stimulating repair activity. ASH1L reduces CPD formation at C-containing but not at TT dinucleotides, and no protection occurs against pyrimidine-(6,4)-pyrimidone photoproducts or cisplatin crosslinks. The diminished CPD induction extends to gene promoters but excludes retrotransposons. This guardian role against CPDs in regulatory elements is associated with the presence of H3K4me3 and H3K27ac histone marks, which are known to interact with the PHD and BRD motifs of ASH1L, respectively. Molecular dynamics simulations identified a DNA-binding AT hook of ASH1L that alters the distance and dihedral angle between neighboring C nucleotides to disfavor dimerization. The loss of this protection results in a higher frequency of C–>T transitions at enhancers of skin cancers carrying ASH1L mutations compared to ASH1L-intact counterparts.

2024-06-02 | GSE260917 | GEO

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

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

| PRJNA942778 | ENA

ASH1L guards cis-regulatory elements against cyclobutane pyrimidine dimer induction [ChIP-seq]

2024-06-02 | GSE261073 | GEO

CPD-seq mapping of transcription-coupled DNA repair in yeast

Project description:Transcription-coupled nucleotide excision repair (TC-NER) is an important DNA repair mechanism that responds to RNA polymerase (RNAP) stalling and removes DNA lesions from transcribed genes. Activation of TC-NER requires specific factors, such as human Cockayne syndrome group B (CSB) protein or its yeast homolog Rad26. Mutations in CSB are associated with the severe neurological disorder Cockayne syndrome. However, the genome-wide role of CSB/Rad26 in TC-NER, particularly in the context of chromatin organization, is not fully understood. Here we used single-nucleotide resolution UV damage mapping data to investigate the genome-wide function of Rad26 in TC-NER. Our data shows that Rad26 is critical for TC-NER in transcribed regions downstream of the first (+1) nucleosome; however, Rad26 is largely dispensable for TC-NER in the +1 nucleosome. We further show that the Rad26-independent TC-NER in the +1 nucleosome is correlated with high occupancy of the transcription initiation/repair factor TFIIH. Downstream of the +1 nucleosome, the combination of low TFIIH occupancy and high occupancy of the transcription elongation factor Spt4/Spt5 suppresses TC-NER when Rad26 is dysfunctional. Deletion of SPT4 significantly restores TC-NER in the downstream nucleosomes in a rad26∆ mutant. Collectively, these data indicate that the requirement for Rad26 in TC-NER is modulated by the distribution of TFIIH and Spt4/Spt5, and Rad26 mainly functions in the downstream nucleosomes to remove TC-NER suppression by Spt4/Spt5.

2020-06-30 | GSE145911 | GEO

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