Dynamic maps of UV damage formation and repair for the human genome

Hu, Jinchuan; Adebali, Ogün; Adar, Sheera; Sancar, Aziz

doi:10.1073/pnas.1706522114

Cited by 165 publications

(271 citation statements)

References 40 publications

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“…T-asymmetry and the difference between genic and non-genic regions are the main results of the Damage-seq experiments 30 that support the utility of the data for the genome-wide analysis of bulky DNA damage and repair by the NER system. Thus, for quality control of the Damage-seq data, we calculated T-asymmetry and the ratio of reads in intergenic and genic regions separately for all replicas.…”

Section: Methodssupporting

confidence: 54%

“…The XR-seq dataset for cyclobutane pyrimidine dimers (CPD) reported in Adar et al 29 allowed us to estimate the amount of DNA damage actively repaired by NER following UV irradiation. To directly assess the presence of unrepaired DNA damage, we used the Damage-seq data for CPDs provided by Hu et al 30 . We did not use XR-seq and Damage-seq data for pyrimidinepyrimidone (6-4) photoproducts because these lesions are repaired too quickly to permit an accurate analysis of the effect of damage bypass over successive rounds of replication.…”

Section: Methodsmentioning

confidence: 99%

“…To test whether the differential activity of the NER system reflects the preferential bypass of DNA damage, we analyze the Damage-seq dataset 30 . Damage-seq detects DNA damage (cyclobutane pyrimidine dimers), and data over a series of time points following the exposure of human fibroblasts to UV radiation are available.…”

mentioning

confidence: 99%

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Error-prone bypass of DNA lesions during lagging strand replication is a common source of germline and cancer mutations

Seplyarskiy

Andrianova

Nikolaev

et al. 2017

Preprint

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Spontaneously occurring mutations are of great relevance in diverse fields including biochemistry, oncology, evolutionary biology, and human genetics. Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity as well as many forms of DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutations remain completely unknown. Here, based on the mutational asymmetry with respect to the direction of replication and transcription, we suggest that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis. Asymmetry with respect to transcription is believed to be mediated by the action of transcription-coupled DNA repair (TC-NER). TC-NER selectively repairs DNA lesions on the transcribed strand; as a result, lesions on the non-transcribed strand are preferentially converted into mutations. In human polymorphism we detect a striking similarity between transcriptional asymmetry and asymmetry with respect to replication fork direction. This parallels the observation that damage-induced mutations in human cancers accumulate asymmetrically with respect to the direction of replication, suggesting that DNA lesions are asymmetrically resolved during replication. Re-analysis of XR-seq data, Damage-seq data and cancers with defective NER corroborate the preferential error-prone bypass of DNA lesions on the lagging strand. We experimentally demonstrate that replication delay greatly attenuates the mutagenic effect of UV-irradiation, in line with the key role of replication in conversion of DNA damage to mutations. We conservatively estimate that at least 10% of human germline mutations arise due to DNA damage rather than replication infidelity. The number of these damage-induced mutations is expected to scale with the number of replications and, consequently, paternal age.

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Section: Methodssupporting

confidence: 54%

Section: Methodsmentioning

confidence: 99%

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Error-prone bypass of DNA lesions during lagging strand replication is a common source of germline and cancer mutations

Seplyarskiy

Andrianova

Nikolaev

et al. 2017

Preprint

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“…Notably, it has been shown that 5mC facilitates CPD formation by UVB (280-315 nm), the main inducer of CPDs in sunlight, but not by UVC (100-280 nm) 25,26 , which does not penetrate the atmosphere. Despite this, genome-wide studies of CPD formation in human cells to date have all been performed using UVC 14,15,27,28 . To address this, we mapped CPDs genome-wide in human A375 melanoma cells immediately following exposure to UVB (310 nm), using a protocol based on T4 endonuclease V digestion and Illumina sequencing as described previously for UVC 15 (Fig.…”

Section: Reduced Pyrimidine Dimer Formation By Uvb In Promoters With mentioning

confidence: 99%

Intragenomic variability and extended sequence patterns in the mutational signature of ultraviolet light

Lindberg

Boström

Elliott

et al. 2019

Preprint

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Mutational signatures can reveal properties of underlying mutational processes and are important when assessing signals of selection in cancer. Here we describe the sequence characteristics of mutations induced by ultraviolet (UV) light, a major mutagen in several human cancers, in terms of extended (longer than trinucleotide) patterns as well as variability of the signature across chromatin states. Promoter regions display a distinct UV signature with reduced TCG>TTG transitions, and genome-wide mapping of UVB-induced DNA photoproducts (pyrimidine dimers) showed that this may be explained by decreased damage formation at hypomethylated promoter CpG sites. Further, an extended signature model encompassing additional information from longer patterns improves modeling of UV mutation rate, which may enhance discrimination between drivers and passenger events. Our study presents a refined picture of the UV signature and underscores that the characteristics of a single mutational process may vary across the genome.

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“…23,26,30 While the thymine dimer T^T CPD opposite its canonical adenine (AA) bases in the complementary strand is NER-resistant, it becomes an excellent substrate of NER when these AA bases are replaced by “mismatched” GG. 10 The development of genome-wide methods of analysis of the formation and repair of these UV photolesions in human fibroblasts, 31 human lymphocytes, 32 and yeast 30 genomes has provided novel insights into the base sequence dependence of mutational processes at the single nucleotide level of resolution.…”

Section: Recognition Of Dna Damage and Initiation Of Gg-nermentioning

confidence: 99%

Repair-Resistant DNA Lesions

Geacintov

Broyde

2017

Chem. Res. Toxicol.

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The eukaryotic global genomic nucleotide excision repair (GG-NER) pathway is the major mechanism that removes most bulky and some nonbulky lesions from cellular DNA. There is growing evidence that certain DNA lesions are repaired slowly or are entirely resistant to repair in cells, tissues, and in cell extract model assay systems. It is well established that the eukaryotic DNA lesion-sensing proteins do not detect the damaged nucleotide, but recognize the distortions/destabilizations in the native DNA structure caused by the damaged nucleotides. In this article, the nature of the structural features of certain bulky DNA lesions that render them resistant to NER, or cause them to be repaired slowly, is compared to that of those that are good-to-excellent NER substrates. Understanding the structural features that distinguish NER-resistant DNA lesions from good NER substrates may be useful for interpreting the biological significance of biomarkers of exposure of human populations to genotoxic environmental chemicals. NER-resistant lesions can survive to replication and cause mutations that can initiate cancer and other diseases. Furthermore, NER diminishes the efficacy of certain chemotherapeutic drugs, and the design of more potent pharmaceuticals that resist repair can be advanced through a better understanding of the structural properties of DNA lesions that engender repair-resistance.

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Dynamic maps of UV damage formation and repair for the human genome

Cited by 165 publications

References 40 publications

Error-prone bypass of DNA lesions during lagging strand replication is a common source of germline and cancer mutations

Error-prone bypass of DNA lesions during lagging strand replication is a common source of germline and cancer mutations

Intragenomic variability and extended sequence patterns in the mutational signature of ultraviolet light

Repair-Resistant DNA Lesions

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