Available online 18 May 2024, 103694

Author links open overlay panel, Highlights•

Defective DNA repair elevates the rates of spontaneous mutagenesis

•

Deficiency of each DNA repair pathway results in distinct patterns of mutations

•

The mechanisms include error-prone alternative repair or replication of damaged DNA

•

The etiology of cancer mutation signatures includes DNA repair deficiencies.

ABSTRACT

Multiple separate repair mechanisms safeguard the genome against various types of DNA damage, and their failure can increase the rate of spontaneous mutagenesis. The malfunction of distinct repair mechanisms leads to genomic instability through different mutagenic processes. For example, defective mismatch repair causes high base substitution rates and microsatellite instability, whereas homologous recombination deficiency is characteristically associated with deletions and chromosome instability. This review presents a comprehensive collection of all mutagenic phenotypes associated with the loss of each DNA repair mechanism, drawing on data from a variety of model organisms and mutagenesis assays, and placing greatest emphasis on systematic analyses of human cancer datasets. We describe the latest theories on the mechanism of each mutagenic process, often explained by reliance on an alternative repair pathway or the error-prone replication of unrepaired, damaged DNA. Aided by the concept of mutational signatures, the genomic phenotypes can be used in cancer diagnosis to identify defective DNA repair pathways.

Section snippetsMutator phenotype, mutation categories and data sources

Studies of DNA replication and repair have been coupled to studies of mutagenesis since the dawn of molecular biology. Mutations are permanent changes in the sequence of genomic DNA, which can arise either due to imprecise replication or due to chemical alterations in the structure of the DNA molecule. Mutagenesis is a two-step process. First, a DNA lesion arises whose nature can range from an incorrectly paired base to a chemical adduct or strand break, then intact double stranded DNA is

The MMR pathway

DNA mismatch repair (MMR) corrects erroneous base pairs and small indels that affect one strand, thereby increasing replication fidelity. The mechanism of MMR has been recently reviewed [22], [23], [24], [25]. Briefly, the recognition of mismatches is ensured by a post-replicative sliding clamp called MutS. MutSα (MSH2/MSH6) recognizes base mismatches and insertion-deletion loops of length 1-3 bp, while MutSβ (MSH2/MSH3) recognizes loops of variable sizes up to 13 bp. The MutS complex recruits

Non-homologous end joining

Non-homologous end joining refers to repair mechanisms that can ligate DNA double strand breaks (DSBs) in an error-prone manner, often with sequence loss. Classical c-NHEJ, reviewed elsewhere [64], [65], is initiated by the rapid binding of the Ku70-Ku80 heterodimer to DNA ends, followed in higher eukaryotes by DNA-dependent protein kinase catalytic subunit (DNA-PKCS). The subsequent recruitment of XLF and the XRCC4-DNA ligase IV complex promotes end synapsis and ligation. Numerous accessory

Homologous recombination

Homologous recombination is a collective term covering multifaceted DNA repair and damage tolerance mechanisms that operate in a cell cycle dependent manner. Functions of HR proteins include the repair of DNA double strand breaks [87], [88], contribution to the repair of DNA interstrand crosslinks [89], [90], the protection of stalled replication forks [91], [92], [93], the salvage of broken replication forks, and the replicative bypass of DNA lesions using a homologous template [94], [95]. The

Interstrand crosslink repair

ICLs can be repaired by multiple mechanisms (see [89] for a recent review). The best studied Fanconi anaemia (FA) pathway employs dedicated complexes of Fanconi proteins as well as factors shared with HR, TLS, and other DNA damage tolerance mechanisms to unhook the crosslink and repair the cut DNA molecule. Alternatively, the NEIL3 glycosylase can unhook the crosslink without creating DNA breaks and leave templates for TLS [138]. FA is a cancer predisposition syndrome. Cells from FA patients

DPC repair

DNA-protein crosslinks (DPCs) are large lesions threatening all aspects of DNA function including transcription, unwinding and replication. There are multiple options for the repair of DPCs including hydrolytic repair by TDP1 and TDP2 specialised for TOP1 and TOP2 crosslinks, MRN-dependent cleavage of DNA leading to clean DSBs to be repaired by NHEJ or occasionally HR, and proteolytic repair via SPRTN and SMT3 (Wss1) leading to a residual peptide excised by NER, reviewed in [143]. Spartan

Base excision repair

DNA bases are prone to chemical damage such as oxidation, alkylation or deamination. The resulting small lesions may not inhibit replication but contribute to mutation fixation by erroneous replication. Base excision repair (BER) is the major pathway for removing modified bases of exogenous and endogenous sources [146], [147]. First, the damaged base is recognised and cleaved by a damage-specific DNA glycosylase resulting in an apurinic or apyrimidic (AP) site; bifunctional glycosylases like

Nucleotide excision repair

NER is specialised for the repair of bulky lesions that affect a single DNA strand. Two separate, evolutionally conserved branches of NER are distinguished by the detection of the lesion. In global genome repair (GG-NER), lesions are initially bound by XPC-RAD23B or by the DDB1-DDB2 complex [170]. In contrast, transcription-coupled repair (TC-NER) relies on the stalling of RNA polymerase II for lesion detection, which is then bound by CSA, CSB and UVSSA to recruit transcription factor IIH

Direct repair

Small lesions in DNA may be repaired without the incision of the DNA backbone through the enzymatic reversion of the lesion to the normal base, providing completely error-free repair [187], [188]. A notable example of direct repair (DR) are photolyases, but these are not present in mammals, and the NER pathway is responsible for the repair of UV photoproducts instead. The ALKBH2 and ALKBH3 α-ketoglutarate-dependent dioxygenases remove the alkyl groups from 1-methyladenine and 3-methylcytosine.

Using the mutational landscape for treatment prediction

DNA repair defects found in cancer can be exploited by targeted therapies (see [19] for a recent review). Beyond repair gene mutations, the genomic imprint of somatic mutations in cancer can be used to diagnose DNA repair deficiencies and select targeted therapies [198], [199]. Bioinformatics tools are being developed for the prediction of DNA damage repair defects based on tumour mutational spectra [200]. In MMR deficiency, the sheer number of genomic mutations is the dominant feature for

Mutagenic repair alternatives or translesion replication

An overarching theme of this review is that the mutagenicity of a DNA repair defect is the consequence of the processing of unrepaired lesions by an alternative, error-prone mechanism. Most commonly, this is replication of the damaged template. This may be performed by regular replicative DNA polymerases over lesions they can accommodate, fixing the mutations at DNA mismatches or introducing mutation-generating mismatches opposite certain base lesions such as 8-oxoG [218]. Alternatively,

CRediT authorship contribution statement

Eszter Németh: Writing – review & editing, Writing – original draft, Funding acquisition, Conceptualization. Dávid Szüts: Writing – review & editing, Writing – original draft, Funding acquisition, Conceptualization.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

ACKNOWLEDGEMENTS

This work was supported by the National Research, Development and Innovation Office of Hungary (NKFIH, grants K134779, K142385 and PharmaLab, RRF-2.3.1-21-2022-00015 to DS; PD134818 to EN). Project no. RRF-2.3.1-21-2022-00015 has been implemented with the support provided by the European Union.

REFERENCES (236)E. Németh et al.Two main mutational processes operate in the absence of DNA mismatch repair

DNA Repair (Amst)

(2020)

N.J. Haradhvala et al.Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair

Cell

(2016)

N.R. Pannunzio et al.Nonhomologous DNA end-joining for repair of DNA double-strand breaks

J Biol Chem

(2018)

M.N. Paddock et al.Competition between PARP-1 and Ku70 control the decision between high-fidelity and mutagenic DNA repair

DNA Repair (Amst)

(2011)

S.F. Bunting et al.53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks

Cell

(2010)

M. Audebert et al.Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining

J Biol Chem

(2004)

A. Schrempf et al.Targeting the DNA Repair Enzyme Polymerase θ in Cancer Therapy

Trends Cancer

(2021)

W.D. Wright et al.Homologous recombination and the repair of DNA double-strand breaks

J Biol Chem

(2018)

S. Tye et al.A fork in the road: Where homologous recombination and stalled replication fork protection part ways

Semin Cell Dev Biol

(2021)

C.M. Kondratick et al.Making Choices: DNA Replication Fork Recovery Mechanisms

Semin Cell Dev Biol

(2021)

N. Chatterjee et al.Mechanisms of DNA damage, repair, and mutagenesis

Environ Mol Mutagen

(2017)

E.C. CoxBacterial mutator genes and the control of spontaneous mutation

Annu Rev Genet

(1976)

L.A. LoebHuman cancers express mutator phenotypes: origin, consequences and targeting

Nat Rev Cancer

(2011)

C. Alkan et al.Genome structural variation discovery and genotyping

Nat Rev Genet

(2011)

C.D. Steele et al.Signatures of copy number alterations in human cancer

Nature

(2022)

L.B. Alexandrov et al.The repertoire of mutational signatures in human cancer

Nature

(2020)

A. Degasperi et al.Substitution mutational signatures in whole-genome-sequenced cancers in the UK population

Science

(2022)

Everall A., Tapinos A., Hawari A., Cornish A., Sud A., Chubb D., Kinnersley B., Frangou A., Barquin M., Jung J., et al:...S. Nik-Zainal et al.Landscape of somatic mutations in 560 breast cancer whole-genome sequences

Nature

(2016)

Y. Li et al.Patterns of somatic structural variation in human cancer genomes

Nature

(2020)

COSMIC: Mutational Signatures (v3.4) http://cancer.sanger.ac.uk/signatures Accessed on 13 March 2024....Signal: https://signal.mutationalsignatures.com/explore/cancer Accessed on 22 March 2024....H.V. MallingHistory of the science of mutagenesis from a personal perspective

Environ Mol Mutagen

(2004)

W. Xiao et al.Toward best practice in cancer mutation detection with whole-genome and whole-exome sequencing

Nat Biotechnol

(2021)

J.L. Hopkins et al.DNA repair defects in cancer and therapeutic opportunities

Genes Dev

(2022)

P.A. Jeggo et al.DNA repair, genome stability and cancer: a historical perspective

Nat Rev Cancer

(2016)

D. Ivanov et al.Experimental systems for the analysis of mutational signatures: no 'one-size-fits-all' solution

Biochem Soc Trans

(2023)

T.A. Kunkel et al.Eukaryotic Mismatch Repair in Relation to DNA Replication

Annu Rev Genet

(2015)

M.C. Olave et al.Mismatch repair deficiency: The what, how and why it is important

Genes Chromosomes Cancer

(2022)

H. Fang et al.Deficiency of replication-independent DNA mismatch repair drives a 5-methylcytosine deamination mutational signature in cancer

Sci Adv

(2021)

G.F. RichardThe Startling Role of Mismatch Repair in Trinucleotide Repeat Expansions

Cells

(2021)

D. Mas-Ponte et al.DNA mismatch repair promotes APOBEC3-mediated diffuse hypermutation in human cancers

Nat Genet

(2020)

D. Mas-Ponte et al.Spectrum of DNA mismatch repair failures viewed through the lens of cancer genomics and implications for therapy

Clin Sci (Lond)

(2022)

S.A. Lujan et al.Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair

Cells

(2021)

I. Cortes-Ciriano et al.A molecular portrait of microsatellite instability across multiple cancers

Nat Commun

(2017)

C.R. Boland et al.A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer

Cancer Res

(1998)

C. Lefol et al.Acquired somatic MMR deficiency is a major cause of MSI tumor in patients suspected for "Lynch-like syndrome" including young patients

Eur J Hum Genet

(2021)

H.T. Tran et al.Hypermutability of homonucleotide runs in mismatch repair and DNA polymerase proofreading yeast mutants

Mol Cell Biol

(1997)

C.N. Greene et al.Frameshift intermediates in homopolymer runs are removed efficiently by yeast mismatch repair proteins

Mol Cell Biol

(1997)

M. Strand et al.Mutations in the MSH3 gene preferentially lead to deletions within tracts of simple repetitive DNA in Saccharomyces cerevisiae

Proc Natl Acad Sci U S A

(1995)

View full text

© 2024 Published by Elsevier B.V.