High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors

Duan, Mingrui; Sivapragasam, Smitha; Antony, Jacob S.; Ulibarri, Jenna; Hinz, John M.; Poon, Gregory M.K.; Wyrick, John J.; Mao, Peng

doi:10.7554/elife.73943

Cited by 8 publications

(4 citation statements)

References 54 publications

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“…A notable exception to this occurs at CTCF binding sites which, like stably bound Reb1 and Abf1 in yeast 50 , generate damage hotspots. Specific nucleotides within the CTCF binding footprint show exceptionally elevated mutation rates, and the absence of increased multiallelic variation at these sites implicates enhanced damage rather than exceptionally suppressed repair.…”

Section: Discussionmentioning

confidence: 99%

Strand-resolved mutagenicity of DNA damage and repair

Anderson

Talmane

Luft

et al. 2022

Preprint

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SummaryDNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here, we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small DNA adducts, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky adducts5. We find that DNA damage tolerance is also common during transcription, where RNA-polymerases frequently bypass lesions without triggering repair. At multiple genomic scales, we show the pattern of DNA damage induced mutations is largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can corrupt the fidelity of nucleotide excision repair and actively drive oncogenic mutagenesis. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance, and repair of DNA damage, thereby shaping cancer genome evolution.

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Section: Discussionmentioning

confidence: 99%

Strand-resolved mutagenicity of DNA damage and repair

Anderson

Talmane

Luft

et al. 2022

Preprint

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“…In contrast, there is little, if any, modulation of 6-4PP formation at a control set of low occupancy Reb1 sites ( SI Appendix , Fig. S9 A ), even though these sites have a nearly identical DNA motif ( 10 , 37 ). Taken together, these data indicate that 6-4PP modulation is specifically associated with Reb1 binding.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide maps of rare and atypical UV photoproducts reveal distinct patterns of damage formation and mutagenesis in yeast chromatin

Bohm

Morledge-Hampton

Stevison

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Ultraviolet (UV) light induces different classes of mutagenic photoproducts in DNA, namely cyclobutane pyrimidine dimers (CPDs), 6-4 photoproducts (6-4PPs), and atypical thymine–adenine photoproducts (TA-PPs). CPD formation is modulated by nucleosomes and transcription factors (TFs), which has important ramifications for Ultraviolet (UV) mutagenesis. How chromatin affects the formation of 6-4PPs and TA-PPs is unclear. Here, we use UV damage endonuclease-sequencing (UVDE-seq) to map these UV photoproducts across the yeast genome. Our results indicate that nucleosomes, the fundamental building block of chromatin, have opposing effects on photoproduct formation. Nucleosomes induce CPDs and 6-4PPs at outward rotational settings in nucleosomal DNA but suppress TA-PPs at these settings. Our data also indicate that DNA binding by different classes of yeast TFs causes lesion-specific hotspots of 6-4PPs or TA-PPs. For example, DNA binding by the TF Rap1 generally suppresses CPD and 6-4PP formation but induces a TA-PP hotspot. Finally, we show that 6-4PP formation is strongly induced at the binding sites of TATA-binding protein (TBP), which is correlated with higher mutation rates in UV-exposed yeast. These results indicate that the formation of 6-4PPs and TA-PPs is modulated by chromatin differently than CPDs and that this may have important implications for UV mutagenesis.

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“…Instead in ASH1L –/– cells, there were 46 million CPDs at 0 h and 45 million by 3 h. Raw dipyrimidine counts were binned into genomic regions of interest and transformed to obtain counts per million reads (CPM) using TMM (Trimmed Mean of M-values) from the edgeR (v.3.34.1) R package (R v.4.1.0). To control for differences due to DNA sequence 6 , 62 , 74 , 75 , CPM from each experimental sample were divided by CPM from the corresponding naked DNA control. To verify the replicability of the HS damage-seq data, we prepared an extra library from an independent culture of U2OS cells harvested immediately after UV irradiation and sequenced this replicate library to approximately half the depth of the original library.…”

Section: Methodsmentioning

confidence: 99%

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

Maritz,

Khaleghi,

Yancoskie

et al. 2023

Nat Commun

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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.

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High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors

Cited by 8 publications

References 54 publications

Strand-resolved mutagenicity of DNA damage and repair

Strand-resolved mutagenicity of DNA damage and repair

Genome-wide maps of rare and atypical UV photoproducts reveal distinct patterns of damage formation and mutagenesis in yeast chromatin

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

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