학술논문
How asymmetric DNA replication achieves symmetrical fidelity
Document Type
Report
Author
Source
Nature Structural and Molecular Biology. December 2021, Vol. 28 Issue 12, p1020, 9 p.
Subject
Language
English
ISSN
1545-9993
Abstract
Author(s): Zhi-Xiong Zhou [sup.1] , Scott A. Lujan [sup.1] , Adam B. Burkholder [sup.2] , Jordan St. Charles [sup.1] , Joseph Dahl [sup.1] , Corinne E. Farrell [sup.1] , Jessica [...]
Accurate DNA replication of an undamaged template depends on polymerase selectivity for matched nucleotides, exonucleolytic proofreading of mismatches, and removal of remaining mismatches via DNA mismatch repair (MMR). DNA polymerases (Pols) [delta] and [epsilon] have 3'-5' exonucleases into which mismatches are partitioned for excision in cis (intrinsic proofreading). Here we provide strong evidence that Pol [delta] can extrinsically proofread mismatches made by itself and those made by Pol [epsilon], independently of both Pol [delta]'s polymerization activity and MMR. Extrinsic proofreading across the genome is remarkably efficient. We report, with unprecedented accuracy, in vivo contributions of nucleotide selectivity, proofreading, and MMR to the fidelity of DNA replication in Saccharomycescerevisiae. We show that extrinsic proofreading by Pol [delta] improves and balances the fidelity of the two DNA strands. Together, we depict a comprehensive picture of how nucleotide selectivity, proofreading, and MMR cooperate to achieve high and symmetrical fidelity on the two strands. Genetic and genomic analyses show that S. cerevisiae DNA polymerase [delta] extrinsically proofreads for errors by polymerase [epsilon] and itself, and demonstrate that the symmetry of replication fidelity is achieved via coordinated efforts of intrinsic and extrinsic proofreading and DNA mismatch repair.
Accurate DNA replication of an undamaged template depends on polymerase selectivity for matched nucleotides, exonucleolytic proofreading of mismatches, and removal of remaining mismatches via DNA mismatch repair (MMR). DNA polymerases (Pols) [delta] and [epsilon] have 3'-5' exonucleases into which mismatches are partitioned for excision in cis (intrinsic proofreading). Here we provide strong evidence that Pol [delta] can extrinsically proofread mismatches made by itself and those made by Pol [epsilon], independently of both Pol [delta]'s polymerization activity and MMR. Extrinsic proofreading across the genome is remarkably efficient. We report, with unprecedented accuracy, in vivo contributions of nucleotide selectivity, proofreading, and MMR to the fidelity of DNA replication in Saccharomycescerevisiae. We show that extrinsic proofreading by Pol [delta] improves and balances the fidelity of the two DNA strands. Together, we depict a comprehensive picture of how nucleotide selectivity, proofreading, and MMR cooperate to achieve high and symmetrical fidelity on the two strands. Genetic and genomic analyses show that S. cerevisiae DNA polymerase [delta] extrinsically proofreads for errors by polymerase [epsilon] and itself, and demonstrate that the symmetry of replication fidelity is achieved via coordinated efforts of intrinsic and extrinsic proofreading and DNA mismatch repair.