Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients
Abstract Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis DNA polymerase η (V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38311-0 |
| _version_ | 1797832015101296640 |
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| author | Andrey A. Yurchenko Fatemeh Rajabi Tirzah Braz-Petta Hiva Fassihi Alan Lehmann Chikako Nishigori Jinxin Wang Ismael Padioleau Konstantin Gunbin Leonardo Panunzi Fanny Morice-Picard Pierre Laplante Caroline Robert Patricia L. Kannouche Carlos F. M. Menck Alain Sarasin Sergey I. Nikolaev |
| author_facet | Andrey A. Yurchenko Fatemeh Rajabi Tirzah Braz-Petta Hiva Fassihi Alan Lehmann Chikako Nishigori Jinxin Wang Ismael Padioleau Konstantin Gunbin Leonardo Panunzi Fanny Morice-Picard Pierre Laplante Caroline Robert Patricia L. Kannouche Carlos F. M. Menck Alain Sarasin Sergey I. Nikolaev |
| author_sort | Andrey A. Yurchenko |
| collection | DOAJ |
| description | Abstract Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis DNA polymerase η (V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyze 38 skin cancer genomes from five XP groups. We find that the activity of NER determines heterogeneity of the mutation rates across skin cancer genomes and that transcription-coupled NER extends beyond the gene boundaries reducing the intergenic mutation rate. Mutational profile in XP-V tumors and experiments with POLH knockout cell line reveal the role of polymerase η in the error-free bypass of (i) rare TpG and TpA DNA lesions, (ii) 3’ nucleotides in pyrimidine dimers, and (iii) TpT photodimers. Our study unravels the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population. |
| first_indexed | 2024-04-09T14:00:57Z |
| format | Article |
| id | doaj.art-43ea5e8dbf97496ea865d7ad15fce1e5 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T14:00:57Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-43ea5e8dbf97496ea865d7ad15fce1e52023-05-07T11:17:05ZengNature PortfolioNature Communications2041-17232023-05-0114111710.1038/s41467-023-38311-0Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patientsAndrey A. Yurchenko0Fatemeh Rajabi1Tirzah Braz-Petta2Hiva Fassihi3Alan Lehmann4Chikako Nishigori5Jinxin Wang6Ismael Padioleau7Konstantin Gunbin8Leonardo Panunzi9Fanny Morice-Picard10Pierre Laplante11Caroline Robert12Patricia L. Kannouche13Carlos F. M. Menck14Alain Sarasin15Sergey I. Nikolaev16INSERM U981, Gustave Roussy Cancer Campus, Université Paris SaclayINSERM U981, Gustave Roussy Cancer Campus, Université Paris SaclayDepartamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, Av. Senador Salgado Filho, s/nNational Xeroderma Pigmentosum Service, Department of Photodermatology, St John’s Institute of Dermatology, Guy’s and St Thomas’ Foundation TrustNational Xeroderma Pigmentosum Service, Department of Photodermatology, St John’s Institute of Dermatology, Guy’s and St Thomas’ Foundation TrustDivision of Dermatology, Department of Internal Related, Kobe University Graduate School of MedicineINSERM U981, Gustave Roussy Cancer Campus, Université Paris SaclayINSERM U981, Gustave Roussy Cancer Campus, Université Paris SaclayINSERM U981, Gustave Roussy Cancer Campus, Université Paris SaclayINSERM U981, Gustave Roussy Cancer Campus, Université Paris SaclayService de Dermatologie, CHU de BordeauxINSERM U981, Gustave Roussy Cancer Campus, Université Paris SaclayINSERM U981, Gustave Roussy Cancer Campus, Université Paris SaclayCNRS UMR9019 Genome Integrity and Cancers, Institut Gustave Roussy, Université Paris-SaclayDepartment of Microbiology, Institute of Biomedical Sciences, University of Sao PauloCNRS UMR9019 Genome Integrity and Cancers, Institut Gustave Roussy, Université Paris-SaclayINSERM U981, Gustave Roussy Cancer Campus, Université Paris SaclayAbstract Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis DNA polymerase η (V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyze 38 skin cancer genomes from five XP groups. We find that the activity of NER determines heterogeneity of the mutation rates across skin cancer genomes and that transcription-coupled NER extends beyond the gene boundaries reducing the intergenic mutation rate. Mutational profile in XP-V tumors and experiments with POLH knockout cell line reveal the role of polymerase η in the error-free bypass of (i) rare TpG and TpA DNA lesions, (ii) 3’ nucleotides in pyrimidine dimers, and (iii) TpT photodimers. Our study unravels the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population.https://doi.org/10.1038/s41467-023-38311-0 |
| spellingShingle | Andrey A. Yurchenko Fatemeh Rajabi Tirzah Braz-Petta Hiva Fassihi Alan Lehmann Chikako Nishigori Jinxin Wang Ismael Padioleau Konstantin Gunbin Leonardo Panunzi Fanny Morice-Picard Pierre Laplante Caroline Robert Patricia L. Kannouche Carlos F. M. Menck Alain Sarasin Sergey I. Nikolaev Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients Nature Communications |
| title | Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients |
| title_full | Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients |
| title_fullStr | Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients |
| title_full_unstemmed | Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients |
| title_short | Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients |
| title_sort | genomic mutation landscape of skin cancers from dna repair deficient xeroderma pigmentosum patients |
| url | https://doi.org/10.1038/s41467-023-38311-0 |
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