Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients

Yurchenko, Andrey A.; Rajabi, Fatemeh; Braz-Petta, Tirzah; Fassihi, Hiva; Lehmann, Alan R.; Nishigori, Chikako; Padioleau, Ismaël; Gunbin, Konstantin; Panunzi, Leonardo; Morice‐Picard, Fanny; Laplante, Pierre; Robert, Caroline; Kannouche, Patricia; Menck, Carlos Frederico Martins; Sarasin, Alain; Nikolaev, Sergey I.

doi:10.1038/s41467-023-38311-0

Cited by 25 publications

(37 citation statements)

References 80 publications

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“…This includes the activities of OGG1-initiated BER, MutY-initiated BER, mismatch repair, nucleotide excision repair (NER), and accurate TLS bypass by DNA polymerase η. We therefore compared spontaneous and KBrO 3 -induced mutation spectra among WT human cell lines and those lacking OGG1 17 , MUTYH 17 , Pol η 47 , or HMCES, a recently identified replication-associated factor that participates in bypass of ssDNA lesions 48–52 and protects cells from cytotoxicity associated with KBrO 3 exposure 48,51 . Loss of OGG1, MUTYH, and HMCES resulted in moderate ∼2 to 3-fold increases in the amount of spontaneously acquired mutations per genome compared to corresponding WT lines, while Pol η-deficiency failed to increase spontaneous mutagenesis (Supplemental Figure 11A).…”

Section: Resultsmentioning

confidence: 99%

“…hTERT-RPE-1 POLH -/-VCF files were available from 47 (Addgene Cat No. 48139) that contain guide RNAs that target the intron-exon junction of the second exon of HMCES (5'-TTGCGCCTACCAGGATCGGC and 5'-ACTTTAGACGGTGGTCACGG).…”

Section: Methodsmentioning

confidence: 99%

“…Full mutation lists used for analysis are available in Supplemental Table 2. hTERT-RPE-1 POLH −/− VCF files were available from 47 available on Mendeley Data server (https://doi.org/10.17632/jkjkpvgxyd.1). MUTYH −/− and OGG1 −/− VCF files were accessed from the supplementary dataset S01 from 17 .…”

Section: Methodsmentioning

confidence: 99%

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Hierarchical determinants of the oxidation-induced mutational landscape in human cells

Cordero,

Mehta,

Weaver

et al. 2024

Preprint

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Abstract8-oxoguanine (8-oxoG) is a common oxidative DNA lesion, which causes G>T substitutions that compose COSMIC single base substitution signature 18 (SBS18) in human cancers. Determinants of local and regional differences in 8-oxoG-induced mutability are currently unknown. To uncover factors influencing the topology of 8-oxoG-induced mutations, we assessed spontaneous and KBrO3-induced 8-oxoG mutagenesis in human cell lines. KBrO3exposure produced a SBS18-like substitution spectrum and a distinct never-before reported INDEL signature that we also observed in human cancers. KBrO3-induced 8-oxoG lesions occurred with similar sequence preference as KBrO3-induced substitutions, indicating that the reactivity of specific reactive oxygen species (ROS) dictates the trinucleotide motif specificity for 8-oxoG-induced mutagenesis. While 8-oxoG lesions occurred relatively uniformly across chromatin states and nucleosomes, 8-oxoG-induced mutations occurred more frequently in more compact regions of the genome, within nucleosomal DNA, and at inward facing guanines within strongly positioned nucleosomes. Cryo-EM structures of OGG1 bound to nucleosomes indicate that these effects originate from OGG1’s ability to flip outward positioned 8-oxoG lesions into the catalytic pocket with only minor alterations to nucleosome structure, while inward facing lesions occluded by the histone octamer are unrecognized. Mutation spectra from cells with DNA repair deficiencies revealed a hierarchical DNA repair network limiting 8-oxoG mutagenesis in human cells, where OGG1– and MUTY-mediated BER is supplemented by replication-associated factors participating in tolerance of 8-oxoG or derived repair intermediates (i.e. Pol η and HMCES). Surprisingly, analysis of transcriptional asymmetry of KBrO3-induced mutations demonstrated transcription-coupled repair of 8-oxoG in Pol η-deficient cells. Thus, radical chemistry, chromatin structures, and DNA repair processes combine to dictate the oxidative mutational landscape in human genomes.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Hierarchical determinants of the oxidation-induced mutational landscape in human cells

Cordero,

Mehta,

Weaver

et al. 2024

Preprint

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“…This conclusion is further supported by analysis of the association of mutation rate and replication timing in xeroderma pigmentosum patients. Patients with severe impairment of the NER lost the association 11 . Interestingly, a recent analysis of the association of replication timing with mutation signatures across 5120 whole-genome sequenced tumors from 40 cancer types did not support this conclusion.…”

Section: Introductionmentioning

confidence: 99%

Both cell autonomous and non-autonomous processes modulate the association between replication timing and mutation rate

Vardi-Yaacov,

Yaacov,

Rosenberg

et al. 2023

Sci Rep

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Cancer somatic mutations are the product of multiple mutational and repair processes, some of which are tightly associated with DNA replication. Mutation rates (MR) are known to be higher in late replication timing (RT) regions, but different processes can affect this association. Systematic analysis of the mutational landscape of 2787 tumors from 32 tumor types revealed that approximately one third of the tumor samples show weak association between replication timing and mutation rate. Further analyses revealed that those samples have unique mutational signatures and are enriched with mutations in genes involved in DNA replication, DNA repair and chromatin structure. Surprisingly, analysis of differentially expressed genes between weak and strong RT-MR association groups revealed that tumors with weak association are enriched with genes associated with cell–cell communication and the immune system, suggesting a non-autonomous response to DNA damage.

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“…The progressive co-development of NGS technologies and cancer genomics databases have enabled the identification of distinct mutational signatures in various cancers, and so far about a half of the identified mutational signatures have underlying processes been assigned to them (1-4). Mutational signatures originate from the effects and interactions of a vast range of environmental and intrinsic sources, such as exposure to chemicals or physical factors like ultraviolet radiation among others, endogenously generated reactive oxygen species (ROS), errors in DNA replication, or defects in specific DNA repair mechanisms (5,6). Elucidating the specific vulnerabilities of cancer cells to different drugs and therapies can facilitate the development of more effective and personalized cancer treatments (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Systematic mutagenesis assay promotes comprehension of the strand-bias laws for mutations induced by oxidative DNA damage

Kawai,

Ebi,

Sugihara

et al. 2024

Preprint

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We have recently developed a systematic and sensitive method for analyzing mutations caused by various environmental and endogenous inducing factors using nucleotide-barcoded supF shuttle vector libraries with a multiplexed NGS assay, namely supF NGS assay. Ionizing radiation-induced cancer is known to be difficult to distinguish from spontaneous cancer, especially in the case of exposing at a lower dose and dose-rate, and discerning the underlying mechanisms of ionizing radiation-induced cancer, especially the relationship between mutagenesis and carcinogenesis, is likely to be an arduous task. In the present study, we have attempted to address the mutations characteristic for exposure to low levels of ionizing radiation using the supF NGS assay. As a result, a significant increase in mutations was detected at cytosines and guanines within 5'-TC-3':5'-GA-3' sites following chronic gamma-irradiation at a dose-rate of 1 Gy per day during 2 days. Since the number of detected mutations exceeded the expectations based on the number of DNA-damages induced by irradiation, we proceeded to explore the possibilities that a single DNA-lesion induced by irradiation may cause amplification of mutations. For this purpose, we utilized the shuttle vector libraries with a single 8-oxo-7,8-dihydroguanine (8-oxo-G)-damaged residue introduced at different sites using an in vitro enzymatic method. Through a set of experiments, we revealed that a single 8-oxo-G-damaged residue can become a trigger for the peripheral mutagenesis; the intense generation of strand-biased mutations occur at 5'-TC-3':5'-GA-3' sites with specific localization in the secondary structures of single-stranded DNA, and more frequently occur at other sites than the 8-oxo-G-damaged sites. Thus, this study provides a novel prospect for the role of a DNA-lesion induced by environmental and endogenous produced ROS in additional mutations. The systematic mutagenesis assay presented in this study will further research to uncover the mechanisms of mutagenesis and the intricacies of that for carcinogenesis.

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Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients

Cited by 25 publications

References 80 publications

Hierarchical determinants of the oxidation-induced mutational landscape in human cells

Hierarchical determinants of the oxidation-induced mutational landscape in human cells

Both cell autonomous and non-autonomous processes modulate the association between replication timing and mutation rate

Systematic mutagenesis assay promotes comprehension of the strand-bias laws for mutations induced by oxidative DNA damage

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