Signatures of TOP1 transcription-associated mutagenesis in cancer and germline

The Genomics England Research Consortium; Colorectal Cancer Domain UK 100,000 Genomes Project

doi:10.1038/s41586-022-04403-y

Signatures of TOP1 transcription-associated mutagenesis in cancer and germline

The Genomics England Research Consortium, Colorectal Cancer Domain UK 100,000 Genomes Project

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Abstract

The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair ¹. In microorganisms, transcription has been demonstrated to be mutagenic ^2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes ⁴. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology ⁵ characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress ⁶, their activity may also be an important source of mutations in the human genome.

Original language	English
Pages (from-to)	623-631
Number of pages	9
Journal	Nature
Volume	602
Issue number	7898
Early online date	9 Feb 2022
DOIs	https://doi.org/10.1038/s41586-022-04403-y
Publication status	Published - 24 Feb 2022

Bibliographical note

Funding Information:
We thank S. Jinks-Robertson for suggesting the traffic light reporter approach; H. Klein for guidance on fluctuation assays; R. van Boxtel for sharing sequencing data for MLH1-KO organoids; A. Bretherick, O. B. Reina and G. Kudla for advice on HygroR re-coding; staff at the IGC core services (L. Murphy, C. Nicol, C. Warnock, E. Freyer, S. Brown and J. Joseph), C. Logan, A. Fluteau, A. Robertson and the staff at Edinburgh Genomics for technical assistance; staff at Liverpool CLL Biobank (funded by Blood Cancer UK) for samples used to generate GEL WGS data; A. Ewing, C.-A. Martin, N. Hastie and W. Bickmore for discussions. Funding for this work: UK Medical Research Council Human Genetics Unit core grants (MC_UU_00007/5 to A.P.J., MC_UU_00007/11 to M.S.T.); Edinburgh Clinical Academic Track PhD programme (Wellcome Trust 204802/Z/16/Z) to T.C.W.; 2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research (grant number 21-40-11-NADE) to F.N.; a CRUK Brain Tumour Centre of Excellence Award (C157/A27589) to M.D.N.; EKFS research grant (2019_A09), Wilhelm Sander-Stiftung (2019.046.1) to K.A., CRUK programme grant (C20807/A2864) to T.S.; La Caixa Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221) to E.C.; E.C. is an Academia Researcher of the Institució Catalana de Recerca i Estudis Avançats of the Generalitat de Catalunya. Edinburgh Genomics is partly supported by NERC (R8/H10/56), MRC (MR/K001744/1) and BBSRC (BB/J004243/1). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.

Publisher Copyright:
© 2022, The Author(s).

Keywords

Animals
DNA Repair/genetics
DNA Topoisomerases, Type I/metabolism
Germ Cells/metabolism
Humans
Mutagenesis/genetics
Mutation
Neoplasms/genetics
Ribonucleotides/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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ReijnsM2022SignaturesFinal published version, 6.98 MBLicence: Creative Commons: Attribution (CC BY)

Cite this

@article{64d4995d9695415182d7889ab961fa4b,

title = "Signatures of TOP1 transcription-associated mutagenesis in cancer and germline",

abstract = "The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair 1. In microorganisms, transcription has been demonstrated to be mutagenic 2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes 4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology 5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress 6, their activity may also be an important source of mutations in the human genome. ",

keywords = "Animals, DNA Repair/genetics, DNA Topoisomerases, Type I/metabolism, Germ Cells/metabolism, Humans, Mutagenesis/genetics, Mutation, Neoplasms/genetics, Ribonucleotides/genetics",

author = "{The Genomics England Research Consortium} and {Colorectal Cancer Domain UK 100,000 Genomes Project} and Reijns, {Martin A. M.} and Parry, {David A.} and Williams, {Thomas C.} and Ferran Nadeu and Hindshaw, {Rebecca L.} and {Rios Szwed}, {Diana O.} and Nicholson, {Michael D.} and Paula Carroll and Shelagh Boyle and Romina Royo and Cornish, {Alex J.} and Hang Xiang and Kate Ridout and Ambrose, {John C.} and Prabhu Arumugam and Roel Bevers and Marta Bleda and Freya Boardman-pretty and Boustred, {Christopher R.} and Helen Brittain and Caulfield, {Mark J.} and Chan, {Georgia C.} and Greg Elgar and Tom Fowler and Adam Giess and Angela Hamblin and Shirley Henderson and Hubbard, {Tim J. P.} and Rob Jackson and Jones, {Louise J.} and Dalia Kasperaviciute and Melis Kayikci and Athanasios Kousathanas and Lea Lahnstein and Leigh, {Sarah E. A.} and Leong, {Ivonne U. S.} and Lopez, {Javier F.} and Fiona Maleady-crowe and Meriel Mcentagart and Federico Minneci and Loukas Moutsianas and Michael Mueller and Nirupa Murugaesu and Need, {Anna C.} and Peter O{\textquoteright}donovan and Eleanor Williams and Ian Tomlinson and Boris Noyvert and Claire Palles and Tatjana Stankovic",

note = "Funding Information: We thank S. Jinks-Robertson for suggesting the traffic light reporter approach; H. Klein for guidance on fluctuation assays; R. van Boxtel for sharing sequencing data for MLH1-KO organoids; A. Bretherick, O. B. Reina and G. Kudla for advice on HygroR re-coding; staff at the IGC core services (L. Murphy, C. Nicol, C. Warnock, E. Freyer, S. Brown and J. Joseph), C. Logan, A. Fluteau, A. Robertson and the staff at Edinburgh Genomics for technical assistance; staff at Liverpool CLL Biobank (funded by Blood Cancer UK) for samples used to generate GEL WGS data; A. Ewing, C.-A. Martin, N. Hastie and W. Bickmore for discussions. Funding for this work: UK Medical Research Council Human Genetics Unit core grants (MC_UU_00007/5 to A.P.J., MC_UU_00007/11 to M.S.T.); Edinburgh Clinical Academic Track PhD programme (Wellcome Trust 204802/Z/16/Z) to T.C.W.; 2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research (grant number 21-40-11-NADE) to F.N.; a CRUK Brain Tumour Centre of Excellence Award (C157/A27589) to M.D.N.; EKFS research grant (2019_A09), Wilhelm Sander-Stiftung (2019.046.1) to K.A., CRUK programme grant (C20807/A2864) to T.S.; La Caixa Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221) to E.C.; E.C. is an Academia Researcher of the Instituci{\'o} Catalana de Recerca i Estudis Avan{\c c}ats of the Generalitat de Catalunya. Edinburgh Genomics is partly supported by NERC (R8/H10/56), MRC (MR/K001744/1) and BBSRC (BB/J004243/1). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. Publisher Copyright: {\textcopyright} 2022, The Author(s). ",

year = "2022",

month = feb,

day = "24",

doi = "10.1038/s41586-022-04403-y",

language = "English",

volume = "602",

pages = "623--631",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7898",

}

TY - JOUR

T1 - Signatures of TOP1 transcription-associated mutagenesis in cancer and germline

AU - The Genomics England Research Consortium

AU - Colorectal Cancer Domain UK 100,000 Genomes Project

AU - Reijns, Martin A. M.

AU - Parry, David A.

AU - Williams, Thomas C.

AU - Nadeu, Ferran

AU - Hindshaw, Rebecca L.

AU - Rios Szwed, Diana O.

AU - Nicholson, Michael D.

AU - Carroll, Paula

AU - Boyle, Shelagh

AU - Royo, Romina

AU - Cornish, Alex J.

AU - Xiang, Hang

AU - Ridout, Kate

AU - Ambrose, John C.

AU - Arumugam, Prabhu

AU - Bevers, Roel

AU - Bleda, Marta

AU - Boardman-pretty, Freya

AU - Boustred, Christopher R.

AU - Brittain, Helen

AU - Caulfield, Mark J.

AU - Chan, Georgia C.

AU - Elgar, Greg

AU - Fowler, Tom

AU - Giess, Adam

AU - Hamblin, Angela

AU - Henderson, Shirley

AU - Hubbard, Tim J. P.

AU - Jackson, Rob

AU - Jones, Louise J.

AU - Kasperaviciute, Dalia

AU - Kayikci, Melis

AU - Kousathanas, Athanasios

AU - Lahnstein, Lea

AU - Leigh, Sarah E. A.

AU - Leong, Ivonne U. S.

AU - Lopez, Javier F.

AU - Maleady-crowe, Fiona

AU - Mcentagart, Meriel

AU - Minneci, Federico

AU - Moutsianas, Loukas

AU - Mueller, Michael

AU - Murugaesu, Nirupa

AU - Need, Anna C.

AU - O’donovan, Peter

AU - Williams, Eleanor

AU - Tomlinson, Ian

AU - Noyvert, Boris

AU - Palles, Claire

AU - Stankovic, Tatjana

N1 - Funding Information: We thank S. Jinks-Robertson for suggesting the traffic light reporter approach; H. Klein for guidance on fluctuation assays; R. van Boxtel for sharing sequencing data for MLH1-KO organoids; A. Bretherick, O. B. Reina and G. Kudla for advice on HygroR re-coding; staff at the IGC core services (L. Murphy, C. Nicol, C. Warnock, E. Freyer, S. Brown and J. Joseph), C. Logan, A. Fluteau, A. Robertson and the staff at Edinburgh Genomics for technical assistance; staff at Liverpool CLL Biobank (funded by Blood Cancer UK) for samples used to generate GEL WGS data; A. Ewing, C.-A. Martin, N. Hastie and W. Bickmore for discussions. Funding for this work: UK Medical Research Council Human Genetics Unit core grants (MC_UU_00007/5 to A.P.J., MC_UU_00007/11 to M.S.T.); Edinburgh Clinical Academic Track PhD programme (Wellcome Trust 204802/Z/16/Z) to T.C.W.; 2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research (grant number 21-40-11-NADE) to F.N.; a CRUK Brain Tumour Centre of Excellence Award (C157/A27589) to M.D.N.; EKFS research grant (2019_A09), Wilhelm Sander-Stiftung (2019.046.1) to K.A., CRUK programme grant (C20807/A2864) to T.S.; La Caixa Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221) to E.C.; E.C. is an Academia Researcher of the Institució Catalana de Recerca i Estudis Avançats of the Generalitat de Catalunya. Edinburgh Genomics is partly supported by NERC (R8/H10/56), MRC (MR/K001744/1) and BBSRC (BB/J004243/1). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. Publisher Copyright: © 2022, The Author(s).

PY - 2022/2/24

Y1 - 2022/2/24

N2 - The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair 1. In microorganisms, transcription has been demonstrated to be mutagenic 2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes 4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology 5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress 6, their activity may also be an important source of mutations in the human genome.

AB - The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair 1. In microorganisms, transcription has been demonstrated to be mutagenic 2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes 4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology 5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress 6, their activity may also be an important source of mutations in the human genome.

KW - Animals

KW - DNA Repair/genetics

KW - DNA Topoisomerases, Type I/metabolism

KW - Germ Cells/metabolism

KW - Humans

KW - Mutagenesis/genetics

KW - Mutation

KW - Neoplasms/genetics

KW - Ribonucleotides/genetics

UR - http://www.scopus.com/inward/record.url?scp=85124726492&partnerID=8YFLogxK

U2 - 10.1038/s41586-022-04403-y

DO - 10.1038/s41586-022-04403-y

M3 - Article

C2 - 35140396

SN - 0028-0836

VL - 602

SP - 623

EP - 631

JO - Nature

JF - Nature

IS - 7898

ER -

Signatures of TOP1 transcription-associated mutagenesis in cancer and germline

Abstract

Bibliographical note

Keywords

UN SDGs

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