SnapShot: DNA Mismatch Repair

Larrea, Andres A.; Lujan, Scott A.; Kunkel, Thomas A.

doi:10.1016/j.cell.2010.05.002

Cited by 94 publications

(67 citation statements)

References 10 publications

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“…In the present study, the frequency of the G allele was 0.78 and therefore high. Zhao et al (2012) argued that the XRCC1 and XRCC3 polymorphisms aff ected the tumor formation in the nerve system, and the XRCC1 and XRCC3 polymorphisms were not related to the digestive system cancers [6,29,30]. Our research indicated that the XRCC3 polymorphism may be sensitive in cancer cases linked to the digestive system.…”

Section: Discussionmentioning

confidence: 73%

Polymorphisms in DNA repair genes XRCC2 and XRCC3 risk of gastric cancer in Turkey

et al. 2014

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We studied the prevalence of polymorphisms in genes XRCC2 and XRCC3 in stomach cancer patients who lived in North Eastern Turkey. A total of 61 cancer patients and 78 controls were included in this study. Single nucleotide changes were studied in XRCC2 and XRCC3 genes at locus Arg188His and Th r241Met. Blood samples were taken from the patients and controls, and DNA was isolated. Th e regions of interest were amplifi ed using a polymerase chain reaction method. After amplifi cation, we used restriction enzymes (HphI and NcoI) to digest the amplifi ed product. Digested product was then run through gel electrophoresis. We identifi ed changes in the nucleotides in these specifi c regions. It was found that the Arg188His polymorphism of the XRCC2 gene was about 39 (24 out of the 61) among cancer patients. However, only 15 (12 out of 78) of the control group indicated this polymorphism. We also observed that 18 of the 61 cancer patients (29) carried the Th r241Met polymorphism of the XRCC3 gene whereas 11 of the 78 (14) individuals in the control group had the polymorphism. Our results showed a signifi cant diff erence in polymorphism ratios between the cancer patients and health control group for the regions of interest. Th is result clearly showed that these polymorphisms increase the risk of stomach cancer and might be a strong marker for early diagnosis of gastric cancer.

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Section: Discussionmentioning

confidence: 73%

Polymorphisms in DNA repair genes XRCC2 and XRCC3 risk of gastric cancer in Turkey

et al. 2014

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“…Considering the frequency of rNMP incorporation by the chromosomal replicase, it seems possible that rNMP residues could signal the newly synthesized strand for MMR, as suggested (2), or cause mutagenesis when imbedded. A role for rNMP residues in MMR is unlikely for E. coli, which has a well-defined MMR system, with a MutH enzyme that nicks the newly synthesized DNA strand at hemimethylated GATC sites to direct repair to the new strand (10,11). RNase HII nicks at single rNMP residues, unlike RNase HI.…”

Section: Resultsmentioning

confidence: 99%

“…Some bacteria (e.g., E. coli) direct MMR using a DNA methylase and MutH endonuclease to recognize and nick the newly replicated strand (1,10,11). However, eukaryotes and most bacteria (e.g., Bacillus subtilis) do not use methyl direction for MMR.…”

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confidence: 99%

Cost of rNTP/dNTP pool imbalance at the replication fork

Yao

Schroeder

Yurieva

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

106

188

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The concentration of ribonucleoside triphosphates (rNTPs) in cells is far greater than the concentration of deoxyribonucleoside triphosphates (dNTPs), and this pool imbalance presents a challenge for DNA polymerases (Pols) to select their proper substrate. This report examines the effect of nucleotide pool imbalance on the rate and fidelity of the Escherichia coli replisome. We find that rNTPs decrease replication fork rate by competing with dNTPs at the active site of the C-family Pol III replicase at a step that does not require correct base-pairing. The effect of rNTPs on Pol rate generalizes to B-family eukaryotic replicases, Pols δ and e. Imbalance of the dNTP pool also slows the replisome and thus is not specific to rNTPs. We observe a measurable frequency of rNMP incorporation that predicts one rNTP incorporated every 2.3 kb during chromosome replication. Given the frequency of rNMP incorporation, the repair of rNMPs is likely rapid. RNase HII nicks DNA at single rNMP residues to initiate replacement with dNMP. Considering that rNMPs will mark the new strand, RNase HII may direct strand-specificity for mismatch repair (MMR). How the newly synthesized strand is recognized for MMR is uncertain in eukaryotes and most bacteria, which lack a methyl-directed nicking system. Here we demonstrate that Bacillus subtilis incorporates rNMPs in vivo, that RNase HII plays a role in their removal, and the RNase HII gene deletion enhances mutagenesis, suggesting a possible role of incorporated rNMPs in MMR.T he structures of ribonucleoside triphosphates (rNTPs) and deoxyribonucleoside triphosphates (dNTPs) differ by a single atom, yet each must be distinguished by DNA and RNA polymerases (Pols). This is more challenging for DNA Pols because the intracellular concentration of rNTPs is 10-100-fold higher than that of dNTPs (1-3). DNA is more stabile than RNA, and rNMP residues in DNA could lead to spontaneous strand breaks. Hence, it is important to genomic integrity that DNA Pols exclude rNMPs from incorporation into the genome (1, 4).Structural studies reveal that DNA Pols distinguish ribo and deoxyribo sugars via a "steric gate," in which a bulky residue or main chain atom sterically occludes binding of the ribo 2′OH (5, 6). However, the single-atom difference between rNTPs and dNTPs imposes an upper limit to sugar recognition, and thus DNA Pols incorporate rNMPs at a low frequency. For example, studies in yeast demonstrate that rNMPs are incorporated in vivo, and studies in vitro demonstrate a frequency of rNMP incorporation predicting that 10,000 rNMPs or more may be incorporated each replication cycle (2,7,8). Given their abundant incorporation, there are probably multiple pathways to remove rNMPs, as their persistence is associated with genomic instability in yeast (7, 9).The current study reconstitutes the Escherichia coli replisome and examines the cost of rNTP/dNTP nucleotide pool imbalance on the frequency of rNMP incorporation and the rate of fork progression. We find that a nucleotide pool imbalance slows the ...

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“…During DNA replication, errors made by DNA polymerases are typically proofread by the 39-59 exonuclease activities that are either intrinsic to the polymerase (Kunkel and Bebenek 2000), or associate with them (Shevelev and Hubscher 2002). Following replication, the mismatch repair (MMR) process ensures that errors made by the DNA polymerase that have not been corrected by the proofreading activity of the polymerase are eliminated rapidly during DNA replication (Kunkel and Bebenek 2000;Jiricny 2006;Hsieh and Yamane 2008;Li 2008;Larrea et al 2010). During protein synthesis, proofreading mechanisms exist not only at the level of tRNAs charging by aminoacyltransferases and during translation (Cochella and Green 2005;Zaher and Green 2009), but also at a second level, by the degradation of nonfunctional polypeptides by various protein machineries, including the proteasome (Ravid and Hochstrasser 2008).…”

Section: Similarities With Other Systems and Remaining Questionsmentioning

confidence: 99%

Proofreading and spellchecking: A two-tier strategy for pre-mRNA splicing quality control

Egecioglu

Chanfreau²

2011

RNA

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Multi-tier strategies exist in many biochemical processes to ensure a maximal fidelity of the reactions. In this review, we focus on the two-tier quality control strategy that ensures the quality of the products of the pre-mRNA splicing reactions catalyzed by the spliceosome. The first step in the quality control process relies on kinetic proofreading mechanisms that are internal to the spliceosome and that are performed by ATP-dependent RNA helicases. The second quality control step, spellchecking, involves recognition of unspliced pre-mRNAs or aberrantly spliced mRNAs that have escaped the first proofreading mechanisms, and subsequent degradation of these molecules by degradative enzymes in the nucleus or in the cytoplasm. This two-tier quality control strategy highlights a need for high fidelity and a requirement for degradative activities that eliminate defective molecules. The presence of multiple quality control activities during splicing underscores the importance of this process in the expression of genetic information.

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SnapShot: DNA Mismatch Repair

Cited by 94 publications

References 10 publications

Polymorphisms in DNA repair genes XRCC2 and XRCC3 risk of gastric cancer in Turkey

Polymorphisms in DNA repair genes XRCC2 and XRCC3 risk of gastric cancer in Turkey

Cost of rNTP/dNTP pool imbalance at the replication fork

Proofreading and spellchecking: A two-tier strategy for pre-mRNA splicing quality control

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