Complex Mutation Profiles in Mismatch Repair and Ribonucleotide Reductase Mutants Reveal Novel Repair Substrate Specificity of MutS Homolog (MSH) Complexes

Na, Lamb; Bard, Judith; Loll-Krippleber, Raphaël; Baryshnikova, Anastasia; Gw, Brown; Surtees, Jennifer A.

doi:10.1101/2021.06.30.450577

Cited by 3 publications

(7 citation statements)

References 84 publications

(267 reference statements)

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“…Abrogation of MutSα function seems to affect both substitution and indel rate (Kunkel and Erie 2015). Although defects in MutSβ function result primarily in defects in repair of short indels (Kunkel and Erie 2015), mutations in Msh3 have been shown using reporter constructs to have an effect on the spectrum of substitution mutations, but not their rate (Harrington and Kolodner 2007; Lamb et al 2021). We do not detect a statistically significant difference in the number of substitutions between msh3 + and msh3 - strains, although the total number of mutations in our study is likely too small to test for an effect of the msh3 - mutation on the spectrum of substitutions.…”

Section: Discussionmentioning

confidence: 99%

“…SSR mutations are caused by polymerase slippage events during replication, and in most cases are normally corrected by the cell’s mismatch repair (MMR) mechanism (Strand et al 1993, 1995). In eukaryotes, mismatches are recognized and repaired by one of two heterodimers: MutSα, consisting of Msh2 and Msh6, which primarily repairs mismatches and single-nucleotide insertions and deletions, and MutSβ, consisting of Msh2 and Msh3, which primarily repairs short insertions and deletions (reviewed in (Kunkel and Erie 2015)), although mutations in Msh3 also result in changes in the spectrum of substitutions (Harrington and Kolodner 2007; Lamb et al 2021). Mutations in the MMR complexes, especially MutSα, play a key role in certain cancers, and are the primary genetic basis of Lynch syndrome, which results in a high rate of colorectal, endometrial, and other cancers (Heinen 2016).…”

Section: Introductionmentioning

confidence: 99%

“…1993, 1995). In eukaryotes, mismatches are recognized and repaired by one of two heterodimers: MutSα, consisting of Msh2p and Msh6p, which primarily repairs mismatches and single-nucleotide insertions and deletions, and MutSβ, consisting of Msh2p and Msh3p, which primarily repairs short insertions and deletions (reviewed in (Kunkel and Erie 2015)), although mutations in MSH3 also result in changes in the spectrum of substitutions (Harrington and Kolodner 2007; Lamb et al . 2022).…”

Section: Introductionmentioning

confidence: 99%

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The rate of spontaneous mutations in yeast deficient for MutSβ function

Plavskin

Biase

Schwarz

et al. 2022

Preprint

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Mutations in simple sequence repeat loci underlie many inherited disorders in humans, and are increasingly recognized as important determinants of natural phenotypic variation. In eukaryotes, mutations in these sequences are primarily repaired by the MutSβ mismatch repair complex. To better understand the role of this complex in mismatch repair and the determinants of simple sequence repeat mutation predisposition, we performed mutation accumulation in yeast strains with abrogated MutSβ function. We demonstrate that mutations in simple sequence repeat loci in the absence of mismatch repair are primarily deletions. We also show that mutations accumulate at drastically different rates in short (<8 bp) and longer repeat loci. These data lend support to a model in which the mismatch repair complex is responsible for repair primarily in longer simple sequence repeats.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The rate of spontaneous mutations in yeast deficient for MutSβ function

Plavskin

Biase

Schwarz

et al. 2022

Preprint

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“…Msh2-Msh6 predominantly binds and directs the repair of single base mispairs (with the exception of C-C mismatches) and 1-2 nt insertion-deletion loops (IDLs) (6-10). Msh2-Msh3 binds and directs repair of some mispairs, including A-A, C-C and T-G (10-12), as well as both short and longer IDLs of up to 16nt in length (13-16). Following mismatch recognition, MutL homologs (Mlh) Mlh1-Mlh3 and/or Mlh1-Pms1 (Pms2 in humans) is recruited by MSH-DNA complexes in an ATP-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

“…In S. cerevisiae, two heterodimer complexes initiate MMR with distinct but partially overlapping binding affinities (5,6). Msh2-Msh6 predominantly binds and directs the repair of single base mispairs (with the exception of C-C mismatches) and 1-2 nt insertion-deletion loops (IDLs) (6)(7)(8)(9)(10). Msh2-Msh3 binds and directs repair of some mispairs, including A-A, C-C and T-G (10)(11)(12), as well as both short and longer IDLs of up to 16nt in length (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Msh2-Msh3 interferes with DNA metabolismin vivo

Medina‐Rivera

Sridharan

Becker

et al. 2022

Preprint

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Mismatch repair (MMR) is a highly conserved repair pathway essential to safeguard the genome from errors that occur during DNA replication. In Saccharomyces cerevisiae, two Msh complexes initiate MMR, either Msh2-Msh3 or Msh2-Msh6. These heterodimeric complexes recognize a number of DNA structures with varying affinities and play critical roles in DNA metabolism outside of post-replicative MMR; they contribute to genome stability through homologous recombination, double strand break repair (DSBR), and the DNA damage response. In contrast to its role in promoting genome stability, Msh2-Msh3 is associated with genome instability through trinucleotide repeat (TNR) expansions. Msh2-Msh3's non-canonical activity in TNR expansions appears to be an unfortunate consequence of its intrinsic ability to bind to distinct DNA structures. Msh2-Msh3 binds to a wide range of DNA structures, including branched intermediates with 3' or 5' ss/ds DNA. Whereas the binding to 3' ssDNA tails leads to repair in a specialized form of DSBR called 3' non-homologous tail removal (3' NHTR), in vitro evidence suggests that Msh2-Msh3 binding to 5' flap structures interferes with the cleavage activity of the structure-specific endonuclease Rad27 (Fen1 in humans). The endonucleolytic function of Rad27 promotes 5' ssDNA flap processing during Okazaki fragment maturation and long-patch base excision repair (LP-BER). Here we show that elevated Msh2-Msh3 levels interfere with both DNA replication and BER in vivo in an expression and ATP-dependent manner, consistent with the hypothesis that protein abundance and ATPase activities in Msh3 are key drivers of Msh2-Msh3-mediated genomic instability.

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MiR-202-3p inhibits the proliferation and metastasis of lung adenocarcinoma cells by targeting RRM2

Cao¹,

Xue²,

Chen³

et al. 2022

Ann Transl Med

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Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer, and its pathogenesis is still unclear. The present study aimed to investigate the role of miR-202-3p and its downstream target gene, ribonucleotide reductase regulatory subunit M2 (RRM2), in the occurrence and development of LUAD and elucidate the correlation between RRM2 and the clinicopathological stage and prognosis of LUAD. Methods:The expression of miR-202-3p was analyzed using the CancerMIRNome database and quantitative polymerase chain reaction (qPCR). The effects of miR-202-3p and RRM2 on the proliferation, migration, and invasion of A549 cells were analyzed. A dual luciferase reporter assay was used to verify the targeting of miR-202-3p and RRM2. Additionally, the correlation between RRM2 expression and clinicopathology was analyzed. Results: (I) MiR-202-3p was lowly expressed in LUAD and the LUAD cell lines. qPCR confirmed that microRNA (miRNA) transfection was effective and sufficient for subsequent experiments. (II) MiR-202-3p inhibited the proliferation, invasion, and migration of LUAD cells. (III) There was a targeting relationship between miR-202-3p and RRM2, and miR-202-3p affected the expression of the RRM2 protein. RRM2 was highly expressed in lung cancer tissue. (IV) RRM2 was associated with the clinicopathological staging of lung cancer. The prognosis of patients with low RRM2 expression was better, and the prognostic sensitivity of RRM2 to lung cancer was high. RRM2 may exert its effects via the Notch pathway. (V) Si-RRM2 inhibited the expression of the RRM2 protein. RRM2 promoted the proliferation, migration, and invasion of LUAD cells. A miR-202-3p inhibitor restored the inhibitory effect of si-RRM2 on LUAD cells. Conclusions: MiR-202-3p was lowly expressed in lung cancer tissue. MiR-202-3p overexpression inhibited the proliferation and metastasis of lung cancer cells. RRM2 was highly expressed in lung cancer tissue and promoted the proliferation and metastasis of lung cancer cells. MiR-202-3p targeted and inhibited RRM2, thereby reducing the proliferation and metastasis of LUAD cells. LUAD patients with low RRM2 expression had a better prognosis, and the expression level of RRM2 was correlated with the clinical characteristics of lung cancer patients.

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Complex Mutation Profiles in Mismatch Repair and Ribonucleotide Reductase Mutants Reveal Novel Repair Substrate Specificity of MutS Homolog (MSH) Complexes

Cited by 3 publications

References 84 publications

The rate of spontaneous mutations in yeast deficient for MutSβ function

The rate of spontaneous mutations in yeast deficient for MutSβ function

Msh2-Msh3 interferes with DNA metabolismin vivo

MiR-202-3p inhibits the proliferation and metastasis of lung adenocarcinoma cells by targeting RRM2

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