Several aspects of the proposal, which aims to expand open access, require serious discussion and, in some cases, a rethink.
Image credit: Dave Cutler (artist).
New Research In
Physical Sciences
Featured Portals
Articles by Topic
Biological Sciences
Featured Portals
Articles by Topic
-
Edited by Allan H. Conney, Rutgers, The State University of New Jersey, Piscataway, NJ, and approved August 7, 2009 (received for review June 30, 2009)
Abstract
Organisms require faithful DNA replication to avoid deleterious mutations. In yeast, replicative leading- and lagging-strand DNA polymerases (Pols ε and δ, respectively) have intrinsic proofreading exonucleases that cooperate with each other and mismatch repair to limit spontaneous mutation to less than 1 per genome per cell division. The relationship of these pathways in mammals and their functions in vivo are unknown. Here we show that mouse Pol ε and δ proofreading suppress discrete mutator and cancer phenotypes. We found that inactivation of Pol ε proofreading elevates base-substitution mutations and accelerates a unique spectrum of spontaneous cancers; the types of tumors are entirely different from those triggered by loss of Pol δ proofreading. Intercrosses of Pol ε-, Pol δ-, and mismatch repair-mutant mice show that Pol ε and δ proofreading act in parallel pathways to prevent spontaneous mutation and cancer. These findings distinguish Pol ε and δ functions in vivo and reveal tissue-specific requirements for DNA replication fidelity.
Footnotes
- 1To whom correspondence should be addressed. E-mail: bradp{at}u.washington.edu
-
Author contributions,: T.M.A., M.O., J.M.B., L.E.H., Y.C., Y.W., J.A.H., R.E.G., and B.D.P. designed research; T.M.A., M.O., J.M.B., L.E.H., Y.C., Y.W., and R.E.G. performed research; R.E.G. contributed new reagents/analytic tools; T.M.A., M.O., J.M.B., L.E.H., Y.C., Y.W., P.M.T., J.A.H., R.E.G., and B.D.P. analyzed data; and T.M.A. and B.D.P. wrote the paper.
-
This article is a PNAS Direct Submission.
-
This article contains supporting information online at www.pnas.org/cgi/content/full/0907147106/DCSupplemental.
DNA polymerase ε and δ proofreading suppress discrete mutator and cancer phenotypes in mice
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Several large or long-lived animals seem strangely resistant to developing cancer. Elucidating the reasons why could lead to promising cancer-fighting strategies in humans.
Image credit: Shutterstock.com/ronnybas frimages.
PNAS Profile of NAS member and biochemist Hao Wu
A study suggests a putative gene-expression hallmark common to monogamous male vertebrates of some species, namely cichlid fishes, dendrobatid frogs, passeroid songbirds, common voles, and deer mice, and identifies 24 candidate genes potentially associated with monogamy.
Image courtesy of Yusan Yang (University of Pittsburgh, Pittsburgh).
Physical and social well-being in old age are linked to self-assessments of life worth, and a spectrum of behavioral, economic, health, and social variables may influence whether aging individuals believe they are leading meaningful lives.
Image courtesy of Pixabay/MabelAmber.
More Articles of This Classification
Biological Sciences
Related Content
Cited by...
- Quantification of somatic mutation flow across individual cell division events by lineage sequencing
- Impact of tobacco-specific nitrosamine-derived DNA adducts on the efficiency and fidelity of DNA replication in human cells
- Mutational signatures of DNA mismatch repair deficiency in C. elegans and human cancers
- Functional Analysis of Cancer-Associated DNA Polymerase {varepsilon} Variants in Saccharomyces cerevisiae
- Personalized Oncology Meets Immunology: The Path toward Precision Immunotherapy
- Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis
- miR-155 Overexpression Promotes Genomic Instability by Reducing High-fidelity Polymerase Delta Expression and Activating Error-Prone DSB Repair
- Formation of interference-sensitive meiotic cross-overs requires sufficient DNA leading-strand elongation
- Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice
- POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer
- dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase {varepsilon} variants
- Colon cancer-associated mutator DNA polymerase {delta} variant causes expansion of dNTP pools increasing its own infidelity
- Yeast DNA Polymerase {epsilon} Catalytic Core and Holoenzyme Have Comparable Catalytic Rates
- Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition
- Colorectal Cancer Cell Lines Are Representative Models of the Main Molecular Subtypes of Primary Cancer
- A Common Cancer-Associated DNA Polymerase {varepsilon} Mutation Causes an Exceptionally Strong Mutator Phenotype, Indicating Fidelity Defects Distinct from Loss of Proofreading
- DNA Replication Error-Induced Extinction of Diploid Yeast
- The Exomes of the NCI-60 Panel: A Genomic Resource for Cancer Biology and Systems Pharmacology
- Emergence of DNA Polymerase {varepsilon} Antimutators That Escape Error-Induced Extinction in Yeast
- Dual role for mammalian DNA polymerase {zeta} in maintaining genome stability and proliferative responses
- Polymerase {varepsilon}1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome")
- Human DNA Polymerase {epsilon} Is Able to Efficiently Extend from Multiple Consecutive Ribonucleotides
- Aneuploidy Drives a Mutator Phenotype in Cancer
- Differential correction of lagging-strand replication errors made by DNA polymerases {alpha} and {delta}
- Regulation of DNA Polymerase POLD4 Influences Genomic Instability in Lung Cancer
- Active Site Mutations in Mammalian DNA Polymerase {delta} Alter Accuracy and Replication Fork Progression
- Increased Mutagenesis and Unique Mutation Signature Associated with Mitotic Gene Conversion
- Genomic Analysis of the 55 kDa Subunit of DNA Polymerase {epsilon} in Human Intracranial Neoplasms
- Abundant ribonucleotide incorporation into DNA by yeast replicative polymerases