title: Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication.
abstract: Tumors with somatic mutations in the proofreading exonuclease domain of DNA polymerase epsilon (POLE-exo*) exhibit a novel mutator phenotype, with markedly elevated TCT→TAT and TCG→TTG mutations and overall mutation frequencies often exceeding 100 mutations/Mb. Here, we identify POLE-exo* tumors in numerous cancers and classify them into two groups, A and B, according to their mutational properties. Group A mutants are found only in POLE, whereas Group B mutants are found in POLE and POLD1 and appear to be nonfunctional. In Group A, cell-free polymerase assays confirm that mutations in the exonuclease domain result in high mutation frequencies with a preference for C→A mutation. We describe the patterns of amino acid substitutions caused by POLE-exo* and compare them to other tumor types. The nucleotide preference of POLE-exo* leads to increased frequencies of recurrent nonsense mutations in key tumor suppressors such as TP53, ATM, and PIK3R1. We further demonstrate that strand-specific mutation patterns arise from some of these POLE-exo* mutants during genome duplication. This is the first direct proof of leading strand-specific replication by human POLE, which has only been demonstrated in yeast so far. Taken together, the extremely high mutation frequency and strand specificity of mutations provide a unique identifier of eukaryotic origins of replication.
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA;
authors.forename: Eve
authors.initials: E
authors.lastname: Shinbrot
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA;
authors.forename: Erin E
authors.initials: EE
authors.lastname: Henninger
authors.affiliation: Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Nils
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA;
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Covington
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA;
authors.forename: A Yasemin
authors.initials: AY
authors.lastname: Göksenin
authors.affiliation: Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA;
authors.forename: Hsu
authors.initials: H
authors.lastname: Chao
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA;
authors.forename: HarshaVardhan
authors.initials: H
authors.lastname: Doddapaneni
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA;
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA;
authors.forename: Zachary F
authors.initials: ZF
authors.lastname: Pursell
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA; wheeler@bcm.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D058543:Class Ia Phosphatidylinositol 3-Kinase; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004257:DNA Polymerase II / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004258:DNA Polymerase III / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D030541:Databases, Genetic; D005092:Exonucleases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D053842:Microsatellite Instability; D008958:Models, Molecular; D020125:Mutation, Missense; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018741:Replication Origin / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D058543:Class Ia Phosphatidylinositol 3-Kinase; D018389:Codon, Nonsense; D004257:DNA Polymerase II; D004258:DNA Polymerase III; D005092:Exonucleases; D019869:Phosphatidylinositol 3-Kinases; D016159:Tumor Suppressor Protein p53; C588001:PIK3R1 protein, human; C576324:ATM protein, human; C434055:POLD1 protein, human