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

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

doi:10.1038/s41467-023-38311-0

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

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

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18 Citations (Scopus)

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.

Original language	English
Article number	2561
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-38311-0
Publication status	Published - 1 Dec 2023
Externally published	Yes

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Yurchenko, A. A., Rajabi, F., Braz-Petta, T., Fassihi, H., Lehmann, A., Nishigori, C., Wang, J., Padioleau, I., Gunbin, K., Panunzi, L., Morice-Picard, F., Laplante, P., Robert, C., Kannouche, P. L., Menck, C. F. M., Sarasin, A., & Nikolaev, S. I. (2023). Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients. Nature Communications, 14(1), Article 2561. https://doi.org/10.1038/s41467-023-38311-0

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title = "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 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{\textquoteright} 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.",

author = "Yurchenko, {Andrey A.} and Fatemeh Rajabi and Tirzah Braz-Petta and Hiva Fassihi and Alan Lehmann and Chikako Nishigori and Jinxin Wang and Ismael Padioleau and Konstantin Gunbin and Leonardo Panunzi and Fanny Morice-Picard and Pierre Laplante and Caroline Robert and Kannouche, {Patricia L.} and Menck, {Carlos F.M.} and Alain Sarasin and Nikolaev, {Sergey I.}",

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Yurchenko, AA, Rajabi, F, Braz-Petta, T, Fassihi, H, Lehmann, A, Nishigori, C, Wang, J, Padioleau, I, Gunbin, K, Panunzi, L, Morice-Picard, F, Laplante, P, Robert, C, Kannouche, PL, Menck, CFM, Sarasin, A & Nikolaev, SI 2023, 'Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients', Nature Communications, vol. 14, no. 1, 2561. https://doi.org/10.1038/s41467-023-38311-0

TY - JOUR

T1 - Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients

AU - Yurchenko, Andrey A.

AU - Rajabi, Fatemeh

AU - Braz-Petta, Tirzah

AU - Fassihi, Hiva

AU - Lehmann, Alan

AU - Nishigori, Chikako

AU - Wang, Jinxin

AU - Padioleau, Ismael

AU - Gunbin, Konstantin

AU - Panunzi, Leonardo

AU - Morice-Picard, Fanny

AU - Laplante, Pierre

AU - Robert, Caroline

AU - Kannouche, Patricia L.

AU - Menck, Carlos F.M.

AU - Sarasin, Alain

AU - Nikolaev, Sergey I.

PY - 2023/12/1

Y1 - 2023/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-023-38311-0

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C2 - 37142601

AN - SCOPUS:85159552387

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2561

ER -

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

Abstract

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