Publications by authors named "T A Kunkel"
Article Synopsis
- Finalization of eukaryotic DNA replication depends on DNA ligase 1 (LIG1) to fix nicks formed during the maturation of Okazaki Fragments.
- Mutations in LIG1's magnesium binding site lead to higher rates of single-base insertions in the genome, particularly when DNA mismatch repair (MMR) is also compromised.
- These mutations show a specific preference for inserting certain nucleotides, highlighting the importance of accurate LIG1 function in preventing DNA errors during replication.
We show that the rates of single base substitutions, additions, and deletions across the nuclear genome are strongly increased in a strain harboring a mutator variant of DNA polymerase α combined with a mutation that inactivates the 3´-5´ exonuclease activity of DNA polymerase δ. Moreover, tetrad dissections attempting to produce a haploid triple mutant lacking Msh6, which is essential for DNA mismatch repair (MMR) of base•base mismatches made during replication, result in tiny colonies that grow very slowly and appear to be aneuploid and/or defective in oxidative metabolism. These observations are consistent with the hypothesis that during initiation of nuclear DNA replication, single-base mismatches made by naturally exonuclease-deficient DNA polymerase α are extrinsically proofread by DNA polymerase δ, such that in the absence of this proofreading, the mutation rate is strongly elevated.
View Article and Find Full Text PDFThe endonuclease activity of Pms1 directs mismatch repair by generating a nick in the newly replicated DNA strand. Inactivating Pms2, the human homologue of yeast Pms1, increases the chances of colorectal and uterine cancers. Here we use whole genome sequencing to show that loss of this endonuclease activity, via the pms1-DE variant, results in strong mutator effects throughout the Saccharomyces cerevisiae genome.
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- * Research identified two genetic variants (P114T and L128V) in patients suspected of mitochondrial disease, which result in less stable SIRT5 protein and lower activity without creating new harmful effects.
- * A mouse model mimicking the P114T mutation demonstrates reduced SIRT5 levels, but does not show significant metabolic or neurological issues, suggesting that these genetic variants alone are unlikely to be the main cause of the neurological problems in patients.
DNA polymerases lambda (Polλ) and mu (Polμ) are X-Family polymerases that participate in DNA double-strand break (DSB) repair by the nonhomologous end-joining pathway (NHEJ). Both polymerases direct synthesis from one DSB end, using template derived from a second DSB end. In this way, they promote the NHEJ ligation step and minimize the sequence loss normally associated with this pathway.
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