Recurrent Noncoding Mutations in Skin Cancers: UV Damage Susceptibility or Repair Inhibition as Primary Driver?

Roberts, Steven A.; Brown, Alexander; Wyrick, John J.

doi:10.1002/bies.201800152

Cited by 12 publications

(16 citation statements)

References 96 publications

(182 reference statements)

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“…Previous studies have indicated that decreased NER activity in regions of heterochromatin (Adar et al 2016;Roberts et al 2019) and near the central dyad axis of the nucleosome (Sabarinathan et al 2016;Brown et al 2018;Pich et al 2018) is associated with elevated somatic mutation rates in skin cancers. We wondered whether lower NER activity on the 3 ′ side of strongly positioned intragenic nucleosomes is associated with increased somatic mutation rates in UV-exposed cancers.…”

Section: Somatic Mutations In Human Melanomas Have An Asymmetric Distmentioning

confidence: 99%

Asymmetric repair of UV damage in nucleosomes imposes a DNA strand polarity on somatic mutations in skin cancer

et al. 2019

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Nucleosomes inhibit excision repair of DNA damage caused by ultraviolet (UV) light, and it has been generally assumed that repair inhibition is equivalent on both sides of the nucleosome dyad. Here, we use genome-wide repair data to show that repair of UV damage in nucleosomes is asymmetric. In yeast, nucleosomes inhibit nucleotide excision repair (NER) of the nontranscribed strand (NTS) of genes in an asymmetric manner, with faster repair of UV damage occurring on the 5 ′ side of the nucleosomal DNA. Analysis of genomic repair data from UV-irradiated human cells indicates that NER activity along the NTS is also elevated on the 5 ′ side of nucleosomes, consistent with the repair asymmetry observed in yeast nucleosomes. Among intergenic nucleosomes, repair activity is elevated on the 5 ′ side of both DNA strands. The distribution of somatic mutations in nucleosomes shows the opposite asymmetry in NER-proficient skin cancers, but not in NER-deficient cancers, indicating that asymmetric repair of nucleosomal DNA imposes a strand polarity on UV mutagenesis. Somatic mutations are enriched on the relatively slow-repairing 3 ′ side of the nucleosomal DNA, particularly at positions where the DNA minor groove faces away from the histone octamer. Asymmetric repair and mutagenesis are likely caused by differential accessibility of the nucleosomal DNA, a consequence of its left-handed wrapping around the histone octamer.

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Section: Somatic Mutations In Human Melanomas Have An Asymmetric Distmentioning

confidence: 99%

Asymmetric repair of UV damage in nucleosomes imposes a DNA strand polarity on somatic mutations in skin cancer

et al. 2019

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“…In some cases, hot spot mutations in noncoding DNA promote carcinogenesis, as is the case for hot spot mutations in the promoter of the telomerase reverse transcriptase ( TERT ) gene (Horn et al, 2013; Huang et al, 2013; Chiba et al, 2017; Heidenreich & Kumar, 2017). However, recent studies have indicated that some hot spot mutations in noncoding DNA may not drive carcinogenesis, but instead function as neutral “passenger” mutations (Fredriksson et al, 2017; Buisson et al, 2019; Roberts et al, 2019). Such “passenger” hot spots are not under selection, but may instead arise from highly mutagenic processes, such as elevated UV damage formation, as occurs at the binding sites of ETS transcription factors (Elliott et al, 2018; Mao et al, 2018; Premi et al, 2019), or inhibition of repair (Poulos et al, 2016; Sabarinathan et al, 2016; Mao & Wyrick, 2019).…”

Section: Introductionmentioning

confidence: 99%

CTCF binding modulates UV damage formation to promote mutation hot spots in melanoma

et al. 2021

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Somatic mutations in DNA‐binding sites for CCCTC‐binding factor (CTCF) are significantly elevated in many cancers. Prior analysis has suggested that elevated mutation rates at CTCF‐binding sites in skin cancers are a consequence of the CTCF‐cohesin complex inhibiting repair of UV damage. Here, we show that CTCF binding modulates the formation of UV damage to induce mutation hot spots. Analysis of genome‐wide CPD‐seq data in UV‐irradiated human cells indicates that formation of UV‐induced cyclobutane pyrimidine dimers (CPDs) is primarily suppressed by CTCF binding but elevated at specific locations within the CTCF motif. Locations of CPD hot spots in the CTCF‐binding motif coincide with mutation hot spots in melanoma. A similar pattern of damage formation is observed at CTCF‐binding sites in vitro, indicating that UV damage modulation is a direct consequence of CTCF binding. We show that CTCF interacts with binding sites containing UV damage and inhibits repair by a model repair enzyme in vitro. Structural analysis and molecular dynamic simulations reveal the molecular mechanism for how CTCF binding modulates CPD formation.

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“…CPDs have been mapped across the genome at a resolution of 200 to 1,000 nt (5,6). Single-nucleotide measurements averaged over ETS family tran-scription factor binding motifs in many genes mutated in melanoma reveal that CPDs are elevated at these positions (21)(22)(23)). Yet the frequency of CPD induction at single-nucleotide resolution across the entire genome remains unknown, as do hotspots and tissue-dependence.…”

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confidence: 99%

Genomic sites hypersensitive to ultraviolet radiation

Premi

Han

Mehta³

et al. 2019

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

113

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If the genome contains outlier sequences extraordinarily sensitive to environmental agents, these would be sentinels for monitoring personal carcinogen exposure and might drive direct changes in cell physiology rather than acting through rare mutations. New methods, adductSeq and freqSeq, provided statistical resolution to quantify rare lesions at single-base resolution across the genome. Primary human melanocytes, but not fibroblasts, carried spontaneous apurinic sites and TG sequence lesions more frequent than ultraviolet (UV)-induced cyclobutane pyrimidine dimers (CPDs). UV exposure revealed hyperhotspots acquiring CPDs up to 170-fold more frequently than the genomic average; these sites were more prevalent in melanocytes. Hyperhotspots were disproportionately located near genes, particularly for RNA-binding proteins, with the most-recurrent hyperhotspots at a fixed position within 2 motifs. One motif occurs at ETS family transcription factor binding sites, known to be UV targets and now shown to be among the most sensitive in the genome, and at sites of mTOR/5′ terminal oligopyrimidine-tract translation regulation. The second occurs at A2–15TTCTY, which developed “dark CPDs” long after UV exposure, repaired CPDs slowly, and had accumulated CPDs prior to the experiment. Motif locations active as hyperhotspots differed between cell types. Melanocyte CPD hyperhotspots aligned precisely with recurrent UV signature mutations in individual gene promoters of melanomas and with known cancer drivers. At sunburn levels of UV exposure, every cell would have a hyperhotspot CPD in each of the ∼20 targeted cell pathways, letting hyperhotspots act as epigenetic marks that create phenome instability; high prevalence favors cooccurring mutations, which would allow tumor evolution to use weak drivers.

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Recurrent Noncoding Mutations in Skin Cancers: UV Damage Susceptibility or Repair Inhibition as Primary Driver?

Cited by 12 publications

References 96 publications

Asymmetric repair of UV damage in nucleosomes imposes a DNA strand polarity on somatic mutations in skin cancer

Asymmetric repair of UV damage in nucleosomes imposes a DNA strand polarity on somatic mutations in skin cancer

CTCF binding modulates UV damage formation to promote mutation hot spots in melanoma

Genomic sites hypersensitive to ultraviolet radiation

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