DNA binding by yeast Mlh1 and Pms1: implications for DNA mismatch repair

Hall, Mark C.; Shcherbakova, Polina V.; Fortune, John M.; Borchers, Christoph H.; Dial, J. Michael; Tomer, Kenneth B.; Kunkel, Thomas A.

doi:10.1093/nar/gkg324

Cited by 54 publications

(85 citation statements)

References 42 publications

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“…Unlike other ND10 proteins that play antiviral roles, MLH1 is required for viral gene expression, and viral growth is inhibited when MLH1 is depleted. MLH1 may bind the incoming viral genome directly, as MLH1 has some affinity for both double-and single-stranded DNA (19). Alternatively, it may associate with viral genomes indirectly.…”

Section: Discussionmentioning

confidence: 99%

DNA Mismatch Repair Proteins Are Required for Efficient Herpes Simplex Virus 1 Replication

Mohni

Mastrocola

Bai

et al. 2011

J Virol

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Herpes simplex virus 1 (HSV-1) is a double-stranded DNA virus that replicates in the nucleus of its human host cell and is known to interact with many cellular DNA repair proteins. In this study, we examined the role of cellular mismatch repair (MMR) proteins in the virus life cycle. Both MSH2 and MLH1 are required for efficient replication of HSV-1 in normal human cells and are localized to viral replication compartments. In addition, a previously reported interaction between MSH6 and ICP8 was confirmed by coimmunoprecipitation and extended to show that UL12 is also present in this complex. We also report for the first time that MLH1 associates with ND10 nuclear bodies and that like other ND10 proteins, MLH1 is recruited to the incoming genome. Knockdown of MLH1 inhibits immediate-early viral gene expression. MSH2, on the other hand, which is generally thought to play a role in mismatch repair at a step prior to that of MLH1, is not recruited to incoming genomes and appears to act at a later step in the viral life cycle. Silencing of MSH2 appears to inhibit early gene expression. Thus, both MLH1 and MSH2 are required but appear to participate in distinct events in the virus life cycle. The observation that MLH1 plays an earlier role in HSV-1 infection than does MSH2 is surprising and may indicate a novel function for MLH1 distinct from its known MSH2-dependent role in mismatch repair.Herpes simplex virus 1 (HSV-1) is a large double-stranded DNA virus that replicates in the nucleus of the host cell. Although cis-and trans-acting functions involved in HSV-1 replication in infected cells have been identified (69), the mechanism of HSV-1 DNA replication remains poorly understood. The appearance of viral genomes in the nucleus might be expected to induce a cellular DNA damage response, and it is now clear that HSV-1 has evolved a complex relationship with the host DNA damage response pathways (33,48,60,66,70,71). During infection, cellular factors that are beneficial to the virus are hijacked and recruited, while other factors and pathways are degraded or inactivated. Previous work from our group and others has shown that the ATR (ATM-and Rad3-related) and DNA-PK (DNA-dependent protein kinase) DNA damage-sensing kinases are attenuated in HSV-1-infected cells, while the ATM (ataxia-telangiectasia-mutated) kinase is activated (31,34,48,50). In addition, other components of the DNA damage repair and response pathways also appear to be beneficial to the virus and are utilized during viral replication (35). Many host cellular DNA damage proteins are known to localize to viral replication compartments (33,48,60,66,71). Furthermore, in a recent proteomic analysis of replication compartments, several DNA repair proteins were identified as potential interacting partners of the viral single-stranded DNA (ssDNA) binding protein ICP8 (66). One such potential interacting partner, the DNA mismatch repair (MMR) protein MSH2, was shown to localize to the replication compartments in infected cells (66).The DNA MMR system is highly c...

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Section: Discussionmentioning

confidence: 99%

DNA Mismatch Repair Proteins Are Required for Efficient Herpes Simplex Virus 1 Replication

Mohni

Mastrocola

Bai

et al. 2011

J Virol

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“…We note that a similar conclusion has been reached for representative eukaryotic MutL homologues. In yeast it has been shown that point mutations in PMS1 (Pms1-K328E) and MLH1 (Mlh1-R273E,R274E), located within a proposed DNA binding groove, increase the mutation frequencies and rates in vivo (41). These proteins also fail to bind DNA in vitro.…”

Section: Discussionmentioning

confidence: 99%

The DNA Binding Activity of MutL Is Required for Methyl-directed Mismatch Repair in Escherichia coli

Robertson

Pattishall

Matson

2006

Journal of Biological Chemistry

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The DNA binding properties of the mismatch repair protein MutL and their importance in the repair process have been controversial for nearly two decades. We have addressed this issue using a point mutant of MutL (MutL-R266E). The biochemical and genetic data suggest that DNA binding by MutL is required for dam methylation-directed mismatch repair. We demonstrate that purified MutL-R266E retains wild-type biochemical properties that do not depend on DNA binding, such as basal ATP hydrolysis in the absence of DNA and the ability to interact with other mismatch repair proteins. However, purified MutL-R266E binds DNA poorly in vitro as compared with MutL, and consistent with this observation, its DNA-dependent biochemical activities, like DNA-stimulated ATP hydrolysis and helicase II stimulation, are severely compromised. In addition, there is a modest effect on stimulation of MutH-catalyzed nicking. Finally, genetic assays show that MutL-R266E has a strong mutator phenotype, demonstrating that the mutant is unable to function in dam methylation-directed mismatch repair in vivo. Methyl-directed mismatch repair (MMR)2 is the primary pathway for correcting replication errors and unwanted recombination events in the Escherichia coli bacterial cell (1-3). Therefore, a functional MMR pathway is essential for ensuring the integrity of the chromosome as well as for maintaining an acceptable cellular mutation rate. The primary components of the bacterial MMR system are the mutator proteins (MutL, MutS, MutH, and UvrD), several exonucleases including Exo I and Exo X (3Ј to 5Ј polarity), Exo VII and RecJ (5Ј to 3Ј polarity) (4 -6), DNA polymerase III, single-stranded DNA-binding protein, and DNA ligase. These proteins act in concert to correct base-base mismatches after passage of the replication fork (7).A current model of MMR (for reviews, see Refs. 2 and 8 -10) posits that the MutS protein recognizes and binds the mismatched base pair followed by the binding of MutL to form a ternary complex (11). In E. coli both of these proteins function as homodimers (12,13). This complex forms an ␣-shaped loop in the DNA (14) that is dependent on ATP and thought to be the mode for communicating the signal from the mismatch to the nearest hemi-methylated d(GATC) site, where MutH binds to provide the strand discrimination essential in methyl-directed mismatch repair. Once the MutS-MutL complex locates a MutHbound hemi-methylated d(GATC) site, MutH is stimulated, presumably by MutL (15,16), to nick the unmethylated DNA strand, resulting in discrimination of the nascent and parental DNA strands (4, 17). The use of the nearest hemi-methylated d(GATC) as the site of MutH-directed incision provides MMR with a bidirectional capability since this site could be located on either side of the mismatch. Helicase II (uvrD gene product) is then loaded on the appropriate strand at the nick and translocates in a 3Ј to 5Ј direction (18), unwinding the DNA duplex until the mismatch has been removed (19). The signal indicating that sufficient DNA has been...

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“…However, the pms1-G882E and pms1-H888 mutations had no detectable effect on Pms1 stability or interaction with Mlh1 as determined with the two-hybrid assay. The Cterminal domain of MutL has been shown to be important for homodimerization (1,12), interactions with MutH and UvrD (25,26), and DNA binding (27). Furthermore, based on the recently solved crystal structure of the COOH-terminus of MutL (23), the residues affected by the pms1 alleles studied here appear to be in an exposed region of the protein and, therefore, may be important for interaction with other proteins and/or DNA during MMR.…”

Section: Discussionmentioning

confidence: 82%

Novel PMS1 Alleles Preferentially Affect the Repair of Primer Strand Loops during DNA Replication

Erdeniz

Dudley

Gealy

et al. 2005

Molecular and Cellular Biology

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Null mutations in DNA mismatch repair (MMR) genes elevate both base substitutions and insertions/ deletions in simple sequence repeats. Data suggest that during replication of simple repeat sequences, polymerase slippage can generate single-strand loops on either the primer or template strand that are subsequently processed by the MMR machinery to prevent insertions and deletions, respectively. In the budding yeast Saccharomyces cerevisiae and mammalian cells, MMR appears to be more efficient at repairing mispairs comprised of loops on the template strand compared to loops on the primer strand. We identified two novel yeast pms1 alleles, pms1-G882E and pms1-H888R, which confer a strong defect in the repair of "primer strand" loops, while maintaining efficient repair of "template strand" loops. Furthermore, these alleles appear to affect equally the repair of 1-nucleotide primer strand loops during both leading-and lagging-strand replication. Interestingly, both pms1 mutants are proficient in the repair of 1-nucleotide loop mispairs in heteroduplex DNA generated during meiotic recombination. Our results suggest that the inherent inefficiency of primer strand loop repair is not simply a mismatch recognition problem but also involves Pms1 and other proteins that are presumed to function downstream of mismatch recognition, such as Mlh1. In addition, the findings reinforce the current view that during mutation avoidance, MMR is associated with the replication apparatus.DNA mismatch repair (MMR) contributes to genomic integrity by repairing mismatches generated during replication, by chemical damage, and as "heteroduplex" intermediates during recombination (7,28,31,35,44). In addition, the MMR system in higher eukaryotes plays a role in response to DNA damage (3,6,7,62). Inherited MMR defects lead to a mutator phenotype, which in humans and mice is associated with increased cancer susceptibility (5,7,13,16,38,50). The MMR system of Escherichia coli has been reconstituted in vitro with purified proteins, including the dedicated proteins MutS, MutL, and MutH (44,56). The MutS protein, a homodimer, first binds the mispair, followed by recruitment of MutL, the endonuclease MutH, the UvrD helicase, four exonucleases, DNA polymerase, and ligase. Together with transient Dammediated hemimethylation, these proteins impose strand specificity that leads to specific repair of the newly replicated strand (10,25,26,43,44,74).In the budding yeast Saccharomyces cerevisiae, six MutS homologues (Msh proteins Msh1 to Msh6) and four MutL homologues (Mlh proteins, Mlh1 to Mlh3, and Pms1) function in various MMR transactions (7,28,31,35). Unlike E. coli, the MutS and MutL activities of budding yeast and mammals are each comprised of heterodimers. Mismatches in nuclear DNA replication intermediates are recognized by the Msh2/Msh6 and Msh2/Msh3 heterodimers, which have partial functional overlap (7,35,42). Msh2/Msh6 operates in the repair of basebase mispairs and 1-nucleotide "insertion/deletion" loops (28,32,41), while Msh2/Msh3 functions ...

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DNA binding by yeast Mlh1 and Pms1: implications for DNA mismatch repair

Cited by 54 publications

References 42 publications

DNA Mismatch Repair Proteins Are Required for Efficient Herpes Simplex Virus 1 Replication

DNA Mismatch Repair Proteins Are Required for Efficient Herpes Simplex Virus 1 Replication

The DNA Binding Activity of MutL Is Required for Methyl-directed Mismatch Repair in Escherichia coli

Novel PMS1 Alleles Preferentially Affect the Repair of Primer Strand Loops during DNA Replication

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