Alleles of the Yeast PMS1 Mismatch-Repair Gene That Differentially Affect Recombination- and Replication-Related Processes

Abstract Mismatch-repair (MMR) systems promote eukaryotic genome stability by removing errors introduced during DNA replication and by inhibiting recombination between nonidentical sequences (spellchecker and antirecombination activities, respectively). Following a common mismatch-recognition step effected by MutS-homologous Msh proteins, homologs of the bacterial MutL ATPase (predominantly the Mlh1p-Pms1p heterodimer in yeast) couple mismatch recognition to the appropriate downstream processing steps. To examine whether the processing steps in the spellchecker and antirecombination pathways might differ, we mutagenized the yeast PMS1 gene and screened for mitotic separation-of-function alleles. Two alleles affecting only the antirecombination function of Pms1p were identified, one of which changed an amino acid within the highly conserved ATPase domain. To more specifically address the role of ATP binding/hydrolysis in MMR-related processes, we examined mutations known to compromise the ATPase activity of Pms1p or Mlh1p with respect to the mitotic spellchecker and antirecombination activities and with respect to the repair of mismatches present in meiotic recombination intermediates. The results of these analyses confirm a differential requirement for the Pms1p ATPase activity in replication vs. recombination processes, while demonstrating that the Mlh1p ATPase activity is important for all examined MMR-related functions.

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Co-Repression of Mismatch Repair Gene Expression by Hypoxia in Cancer Cells: Role of the Myc/Max Network

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2007.07.1928 ◽

2007 ◽

Vol 69 (3) ◽

pp. S613

Author(s):

R.S. Bindra ◽

P.M. Glazer

Keyword(s):

Gene Expression ◽

Cancer Cells ◽

Mismatch Repair ◽

Mismatch Repair Gene ◽

Repair Gene

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Hypothesis: Possible role of retinoic acid therapy in patients with biallelic mismatch repair gene defects

European Journal of Pediatrics ◽

10.1007/s00431-007-0474-3 ◽

2007 ◽

Vol 167 (2) ◽

pp. 225-229 ◽

Cited By ~ 14

Author(s):

Sven Gottschling ◽

Harald Reinhard ◽

Constanze Pagenstecher ◽

Stefan Krüger ◽

Jochen Raedle ◽

...

Keyword(s):

Retinoic Acid ◽

Mismatch Repair ◽

Mismatch Repair Gene ◽

Repair Gene ◽

Acid Therapy ◽

Gene Defects

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Mismatch Repair: From Preserving Genome Stability to Enabling Mutation Studies in Real-Time Single Cells

Cells ◽

10.3390/cells10061535 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1535

Author(s):

Marina Elez

Keyword(s):

Real Time ◽

Mismatch Repair ◽

Genetic Information ◽

Genome Stability ◽

Direct Evidence ◽

Single Cells ◽

Living Cells ◽

Spontaneous Mutations ◽

Mismatch Recognition

Mismatch Repair (MMR) is an important and conserved keeper of the maintenance of genetic information. Miroslav Radman’s contributions to the field of MMR are multiple and tremendous. One of the most notable was to provide, along with Bob Wagner and Matthew Meselson, the first direct evidence for the existence of the methyl-directed MMR. The purpose of this review is to outline several aspects and biological implications of MMR that his work has helped unveil, including the role of MMR during replication and recombination editing, and the current understanding of its mechanism. The review also summarizes recent discoveries related to the visualization of MMR components and discusses how it has helped shape our understanding of the coupling of mismatch recognition to replication. Finally, the author explains how visualization of MMR components has paved the way to the study of spontaneous mutations in living cells in real time.

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Spontaneously Arising mutL Mutators in Evolving Escherichia coli Populations Are the Result of Changes in Repeat Length

Journal of Bacteriology ◽

10.1128/jb.185.20.6076-6082.2003 ◽

2003 ◽

Vol 185 (20) ◽

pp. 6076-6082 ◽

Cited By ~ 35

Author(s):

Aaron C. Shaver ◽

Paul D. Sniegowski

Keyword(s):

Escherichia Coli ◽

Mismatch Repair ◽

Mutation Rate ◽

Mismatch Repair Gene ◽

Dna Repeats ◽

Wild Type ◽

Repair Gene ◽

Mutator Strains ◽

Experimental Populations

ABSTRACT Over the course of thousands of generations of growth in a glucose-limited environment, 3 of 12 experimental populations of Escherichia coli spontaneously and independently evolved greatly increased mutation rates. In two of the populations, the mutations responsible for this increased mutation rate lie in the same region of the mismatch repair gene mutL. In this region, a 6-bp repeat is present in three copies in the gene of the wild-type ancestor of the experimental populations but is present in four copies in one of the experimental populations and two copies in the other. These in-frame mutations either add or delete the amino acid sequence LA in the MutL protein. We determined that the replacement of the wild-type sequence with either of these mutations was sufficient to increase the mutation rate of the wild-type strain to a level comparable to that of the mutator strains. Complementation of strains bearing the mutator mutations with wild-type copies of either mutL or the mismatch repair gene uvrD rescued the wild-type mutation rate. The position of the mutator mutations—in the region of MutL known as the ATP lid—suggests a possible deficiency in MutL's ATPase activity as the cause of the mutator phenotype. The similarity of the two mutator mutations (despite the independent evolutionary histories of the populations that gave rise to them) leads to a discussion of the potential adaptive role of DNA repeats.

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