Human mismatch repair system balances mutation rates between strands by removing more mismatches from the lagging strand

Mismatch repair (MMR) is one of the main systems maintaining fidelity of replication. Differences in correction of errors produced during replication of the leading and the lagging DNA strands were reported in yeast and in human cancers, but the causes of these differences remain unclear. Here, we analyze data on human cancers with somatic mutations in two of the major DNA polymerases, delta and epsilon, that replicate the genome. We show that these cancers demonstrate a substantial asymmetry of the mutations between the leading and the lagging strands. The direction of this asymmetry is the opposite between cancers with mutated polymerases delta and epsilon, consistent with the role of these polymerases in replication of the lagging and the leading strands in human cells, respectively. Moreover, the direction of strand asymmetry observed in cancers with mutated polymerase delta is similar to that observed in MMR-deficient cancers. Together, these data indicate that polymerase delta (possibly together with polymerase alpha) contributes more mismatches during replication than its leading-strand counterpart, polymerase epsilon; that most of these mismatches are repaired by the MMR system; and that MMR repairs about three times more mismatches produced in cells during lagging strand replication compared with the leading strand.

[1]  P. Timpson.  Faculty Opinions recommendation of The topography of mutational processes in breast cancer genomes. , 2018, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[2]  Jakub Tomek,et al.  Widespread impact of DNA replication on mutational mechanisms in cancer , 2017, bioRxiv.

[3]  J. Diffley,et al.  How the Eukaryotic Replisome Achieves Rapid and Efficient DNA Replication , 2017, Molecular cell.

[4]  G. Bazykin,et al.  APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context , 2016, bioRxiv.

[5]  B. Taylor,et al.  deconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution , 2016, Genome Biology.

[6]  T. Kunkel,et al.  Who Is Leading the Replication Fork, Pol ε or Pol δ? , 2016, Molecular cell.

[7]  S. Antonarakis,et al.  APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication , 2016, Genome research.

[8]  P. Hanawalt,et al.  Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair , 2016, Cell.

[9]  Y. D'Aubenton-Carafa,et al.  Replication landscape of the human genome , 2016, Nature Communications.

[10]  T. Kunkel,et al.  Eukaryotic genome instability in light of asymmetric DNA replication , 2016, Critical reviews in biochemistry and molecular biology.

[11]  M. Stratton,et al.  Clock-like mutational processes in human somatic cells , 2015, Nature Genetics.

[12]  J. Biteen,et al.  Single-molecule motions and interactions in live cells reveal target search dynamics in mismatch repair , 2015, Proceedings of the National Academy of Sciences.

[13]  C. Sander,et al.  Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis. , 2015, Neuro-oncology.

[14]  Robert E. Johnson,et al.  A Major Role of DNA Polymerase δ in Replication of Both the Leading and Lagging DNA Strands. , 2015, Molecular cell.

[15]  T. Kunkel,et al.  Quantifying the contributions of base selectivity, proofreading and mismatch repair to nuclear DNA replication in Saccharomyces cerevisiae. , 2015, DNA repair.

[16]  M. O’Donnell,et al.  Reconstitution of a eukaryotic replisome reveals suppression mechanisms that define leading/lagging strand operation , 2015, eLife.

[17]  T. Kunkel,et al.  Differences in genome-wide repeat sequence instability conferred by proofreading and mismatch repair defects , 2015, Nucleic acids research.

[18]  Y. Kow,et al.  Replicative DNA Polymerase δ but Not ε Proofreads Errors in Cis and in Trans , 2015, PLoS genetics.

[19]  Roland Arnold,et al.  Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers , 2015, Nature Genetics.

[20]  Ben Lehner,et al.  Differential DNA mismatch repair underlies mutation rate variation across the human genome , 2015, Nature.

[21]  Martin A. M. Reijns,et al.  Lagging strand replication shapes the mutational landscape of the genome , 2015, Nature.

[22]  T. Kunkel,et al.  Tracking replication enzymology in vivo by genome-wide mapping of ribonucleotide incorporation , 2014, Nature Structural &Molecular Biology.

[23]  Junhong Han,et al.  Strand-specific analysis shows protein binding at replication forks and PCNA unloading from lagging strands when forks stall. , 2014, Molecular cell.

[24]  T. Kunkel,et al.  Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition , 2014, Genome research.

[25]  Chris Sander,et al.  Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication , 2014, Genome research.

[26]  M. O’Donnell,et al.  CMG helicase and DNA polymerase ε form a functional 15-subunit holoenzyme for eukaryotic leading-strand DNA replication , 2014, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. O’Donnell,et al.  Mechanism of asymmetric polymerase assembly at the eukaryotic replication fork , 2014, Nature Structural &Molecular Biology.

[28]  Z. Pursell,et al.  DNA polymerase ε and its roles in genome stability , 2014, IUBMB life.

[29]  David T. W. Jones,et al.  Signatures of mutational processes in human cancer , 2013, Nature.

[30]  Wei Yang,et al.  The Histone Mark H3K36me3 Regulates Human DNA Mismatch Repair through Its Interaction with MutSα , 2013, Cell.

[31]  A. Sivachenko,et al.  Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples , 2013, Nature Biotechnology.

[32]  Paz Polak,et al.  Differential relationship of DNA replication timing to different forms of human mutation and variation. , 2012, American journal of human genetics.

[33]  T. Kunkel,et al.  Mismatch Repair Balances Leading and Lagging Strand DNA Replication Fidelity , 2012, PLoS genetics.

[34]  Benjamin Audit,et al.  Replication Fork Polarity Gradients Revealed by Megabase-Sized U-Shaped Replication Timing Domains in Human Cell Lines , 2012, PLoS Comput. Biol..

[35]  R. Kolodner,et al.  Mismatch Repair, But Not Heteroduplex Rejection, Is Temporally Coupled to DNA Replication , 2011, Science.

[36]  T. Kunkel.  Balancing eukaryotic replication asymmetry with replication fidelity. , 2011, Current opinion in chemical biology.

[37]  Alain Arneodo,et al.  Replication-associated mutational asymmetry in the human genome. , 2011, Molecular biology and evolution.

[38]  Z. Pursell,et al.  The high fidelity and unique error signature of human DNA polymerase ε , 2010, Nucleic acids research.

[39]  Andres A. Larrea,et al.  Genome-wide model for the normal eukaryotic DNA replication fork , 2010, Proceedings of the National Academy of Sciences.

[40]  P. Modrich,et al.  PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair , 2010, Proceedings of the National Academy of Sciences.

[41]  T. Kunkel,et al.  Dividing the workload at a eukaryotic replication fork. , 2008, Trends in cell biology.

[42]  T. Kunkel,et al.  Division of labor at the eukaryotic replication fork. , 2008, Molecular cell.

[43]  T. Kunkel,et al.  Yeast DNA Polymerase ε Participates in Leading-Strand DNA Replication , 2007, Science.

[44]  T. Kunkel,et al.  Evidence that Errors Made by DNA Polymerase α are Corrected by DNA Polymerase δ , 2006, Current Biology.

[45]  T. Kunkel,et al.  Unique Error Signature of the Four-subunit Yeast DNA Polymerase ϵ* , 2003, Journal of Biological Chemistry.

[46]  J. Palazzo,et al.  MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. , 1999, Human molecular genetics.

[47]  T. Kunkel.  Evolving views of DNA replication (in)fidelity. , 2009, Cold Spring Harbor symposia on quantitative biology.

[48]  Erik Johansson,et al.  HIGH FIDELITY FOR BASE SUBSTITUTIONS BUT LOWER FIDELITY FOR SINGLE- AND MULTI-BASE DELETIONS* , 2005 .