Faculty Opinions recommendation of The impact of sequence divergence and DNA mismatch repair on homeologous recombination in Arabidopsis.

2019 ◽  
Author(s):  
Andrew Paterson
Keyword(s):  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Sequence Divergence ◽  
Dna Mismatch ◽  
Homeologous Recombination ◽  
The Impact

Induction of recombination between homologous and diverged DNAs by double-strand gaps and breaks and role of mismatch repair

1994 ◽  
Vol 14 (7) ◽  
pp. 4802-4814
Author(s):  
S D Priebe ◽  
J Westmoreland ◽  
T Nilsson-Tillgren ◽  
M A Resnick
Keyword(s):  
Gene Conversion ◽  
Mismatch Repair ◽  
Sequence Divergence ◽  
Strand Break ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Heteroduplex Dna ◽  
Dna Mismatch ◽  
Spontaneous Recombination ◽  
The Impact

Sequence homology is expected to influence recombination. To further understand mechanisms of recombination and the impact of reduced homology, we examined recombination during transformation between plasmid-borne DNA flanking a double-strand break (DSB) or gap and its chromosomal homolog. Previous reports have concentrated on spontaneous recombination or initiation by undefined lesions. Sequence divergence of approximately 16% reduced transformation frequencies by at least 10-fold. Gene conversion patterns associated with double-strand gap repair of episomal plasmids or with plasmid integration were analyzed by restriction endonuclease mapping and DNA sequencing. For episomal plasmids carrying homeologous DNA, at least one input end was always preserved beyond 10 bp, whereas for plasmids carrying homologous DNA, both input ends were converted beyond 80 bp in 60% of the transformants. The system allowed the recovery of transformants carrying mixtures of recombinant molecules that might arise if heteroduplex DNA--a presumed recombination intermediate--escapes mismatch repair. Gene conversion involving homologous DNAs frequently involved DNA mismatch repair, directed to a broken strand. A mutation in the PMS1 mismatch repair gene significantly increased the fraction of transformants carrying a mixture of plasmids for homologous DNAs, indicating that PMS1 can participate in DSB-initiated recombination. Since nearly all transformants involving homeologous DNAs carried a single recombinant plasmid in both Pms+ and Pms- strains, stable heteroduplex DNA appears less likely than for homologous DNAs. Regardless of homology, gene conversion does not appear to occur by nucleolytic expansion of a DSB to a gap prior to recombination. The results with homeologous DNAs are consistent with a recombinational repair model that we propose does not require the formation of stable heteroduplex DNA but instead involves other homology-dependent interactions that allow recombination-dependent DNA synthesis.

Mutations in the proapoptotic BAX gene are associated with defective DNA mismatch repair and altered tumor growth rates in human colon cancers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10529-10529
Author(s):  
F. Sinicrope ◽  
R. L. Rego ◽  
A. J. French ◽  
N. R. Foster ◽  
D. J. Sargent ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Caspase 3 ◽  
Dna Mismatch Repair ◽  
Univariate Analysis ◽  
Human Colon ◽  
Wild Type ◽  
Ki 67 ◽  
Dna Mismatch ◽  
Colon Cancers ◽  
The Impact

10529 Background: BAX mutations are associated with defective DNA mismatch repair (MMR) in human colon cancers. However, the impact of BAX inactivation upon tumor cell apoptosis and proliferation in vivo remain unknown. We analyzed and compared caspase-3 and Ki-67 expression in tumors with and without BAX mutations. Methods: TNM stage II and III (n= 377) colon carcinomas were studied from participants in a 5-FU-based adjuvant therapy trial. Archival tumors were analyzed for instability at the BAT26 mononucleotide locus using polymerase chain reaction and hMLH1, hMSH2 and hMSH6 by immunohistochemistry (IHC). Frameshift mutations in a tract of eight deoxyguanosines within BAX were analyzed. Expression of caspase-3 and Ki-67 proteins were analyzed by IHC. Results: Thirty-nine of 377 (10%) tumors showed defective MMR defined as instability at BAT26 and loss of either hMLH1, hMSH2 and/or hMSH6 proteins. BAX mutations were found in 20 of 37 (54%) MMR deficient tumors and in 1 of 50 (2%) tumors with intact MMR. Mean and median number of caspase-3-positive cells were increased in tumors with defective MMR (p= 0.04), but did not differ based upon BAX status [ Table ]. However, tumors with BAX mutations showed higher Ki-67 labeling indices compared to those with wild type BAX (p= 0.01)[ Table ]. Neither BAX mutations nor caspase-3- positive cells were prognostic in a univariate analysis. Tumors with lower Ki-67 extent had improved overall survival (p=0.06), but not DFS (p=0.24). Defective MMR (vs intact) was associated with better DFS in a multivariate analysis (p= 0.03). Conclusion: MMR deficient colon cancers show frequent BAX inactivation, yet have increased apoptotic rates as indicated by increased caspase-3 expressing tumor cells. BAX mutation was associated with hyperproliferation suggesting a growth advantage compared to wild type tumors. [Table: see text] No significant financial relationships to disclose.

scholarly journals CBMT-16. EGFRvIII EXPRESSION CONFERS CHEMOSENSITIVITY BY INCREASING DNA MISMATCH REPAIR PROTEIN EXPRESSION AND REPLICATION STRESS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi36-vi36
Author(s):  
Nina Struve ◽  
Zev A Binder ◽  
Lucy F Stead ◽  
Tim Brend ◽  
Stephen J Bagley ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Expression ◽  
Treatment Response ◽  
Mismatch Repair ◽  
Cell Lines ◽  
Dna Mismatch Repair ◽  
Replication Stress ◽  
Dna Mismatch ◽  
Mgmt Promoter ◽  
The Impact

Abstract MGMT promoter methylation is the only accepted biomarker with prognostic role in GBM but its routine implementation is limited partly response to TMZ is heterogeneous, but also due to lack of effective alternative treatment options. Therefore, additional biomarkers are needed to enable better prediction of survival and to improve individualized treatment of GBM patients. A potential new biomarker is the epidermal growth factor receptor variant III (EGFRvIII). This constitutively activated deletion variant is present in approximately one third of all IDH wildtype GBM, but its relevance to treatment response is poorly understood. The aim of the present study was to analyze the impact of endogenous EGFRvIII expression on chemosensitivity and the mechanisms underlying any differential treatment response. EGFRvIII expression was associated with prolonged median overall survival but only for GBM patients with MGMT promoter methylated tumors. In line with this, we observed increased TMZ sensitivity of EGFRvIII+ and MGMT promoter methylated cells, which translated into improved survival in xenograft experiments. The increased TMZ sensitivity was associated with an elevated DNA damage induction accompanied by an increased expression of DNA mismatch repair (MMR) proteins in EGFRvIII+ cell lines and EGFRvIII+ GBM patient samples. Subsequently, only a moderate reduction in MMR protein expression resulted in a dramatic TMZ resistance, suggesting that EGFRvIII expression specifically sensitized MGMT deficient cells to TMZ treatment by upregulating MMR. Furthermore, EGFRvIII expression in GBM cell lines was accompanied by increased DNA damage, replication fork slowing, stalling and enhanced origin firing, implying replication stress. Targeting of EGFRvIII-dependent replication stress by irinotecan led to hypersensitivity of EGFRvIII+ cells. Taken together this study illustrates that EGFRvIII-induced upregulation of MMR and replication stress increases chemosensitivity thereby highlighting the vulnerability of EGFRvIII+ GBM to available treatments. These important data may also guide the development of new and more effective personalized strategies.

scholarly journals Induction of recombination between homologous and diverged DNAs by double-strand gaps and breaks and role of mismatch repair.

1994 ◽  
Vol 14 (7) ◽  
pp. 4802-4814 ◽  
Author(s):  
S D Priebe ◽  
J Westmoreland ◽  
T Nilsson-Tillgren ◽  
M A Resnick
Keyword(s):  
Gene Conversion ◽  
Mismatch Repair ◽  
Sequence Divergence ◽  
Strand Break ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Heteroduplex Dna ◽  
Dna Mismatch ◽  
Spontaneous Recombination ◽  
The Impact

Sequence homology is expected to influence recombination. To further understand mechanisms of recombination and the impact of reduced homology, we examined recombination during transformation between plasmid-borne DNA flanking a double-strand break (DSB) or gap and its chromosomal homolog. Previous reports have concentrated on spontaneous recombination or initiation by undefined lesions. Sequence divergence of approximately 16% reduced transformation frequencies by at least 10-fold. Gene conversion patterns associated with double-strand gap repair of episomal plasmids or with plasmid integration were analyzed by restriction endonuclease mapping and DNA sequencing. For episomal plasmids carrying homeologous DNA, at least one input end was always preserved beyond 10 bp, whereas for plasmids carrying homologous DNA, both input ends were converted beyond 80 bp in 60% of the transformants. The system allowed the recovery of transformants carrying mixtures of recombinant molecules that might arise if heteroduplex DNA--a presumed recombination intermediate--escapes mismatch repair. Gene conversion involving homologous DNAs frequently involved DNA mismatch repair, directed to a broken strand. A mutation in the PMS1 mismatch repair gene significantly increased the fraction of transformants carrying a mixture of plasmids for homologous DNAs, indicating that PMS1 can participate in DSB-initiated recombination. Since nearly all transformants involving homeologous DNAs carried a single recombinant plasmid in both Pms+ and Pms- strains, stable heteroduplex DNA appears less likely than for homologous DNAs. Regardless of homology, gene conversion does not appear to occur by nucleolytic expansion of a DSB to a gap prior to recombination. The results with homeologous DNAs are consistent with a recombinational repair model that we propose does not require the formation of stable heteroduplex DNA but instead involves other homology-dependent interactions that allow recombination-dependent DNA synthesis.

scholarly journals Absence of Azole or Echinocandin Resistance inCandida glabrataIsolates in India despite Background Prevalence of Strains with Defects in the DNA Mismatch Repair Pathway

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Ashutosh Singh ◽  
Kelley R. Healey ◽  
Priyanka Yadav ◽  
Gargi Upadhyaya ◽  
Neelam Sachdeva ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Geometric Mean ◽  
Antifungal Susceptibility ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
The Novel ◽  
Content Type ◽  
Dna Mismatch ◽  
The Impact

ABSTRACTCandida glabratainfections are increasing worldwide and exhibit greater rates of antifungal resistance than those with other species. DNA mismatch repair (MMR) gene deletions, such asmsh2Δ, inC. glabrataresulting in a mutator phenotype have recently been reported to facilitate rapid acquisition of antifungal resistance. This study determined the antifungal susceptibility profiles of 210C. glabrataisolates in 10 hospitals in India and investigated the impact of novelMSH2polymorphisms on mutation potential. No echinocandin- or azole-resistant strains and no mutations inFKShot spot regions were detected among theC. glabrataisolates, supporting ourin vitrosusceptibility testing results. CLSI antifungal susceptibility data showed that the MICs of anidulafungin (geometric mean [GM], 0.12 μg/ml) and micafungin (GM, 0.01 μg/ml) were lower and below the susceptibility breakpoint compared to that of caspofungin (CAS) (GM, 1.31 μg/ml). Interestingly, 69% of theC. glabratastrains sequenced contained six nonsynonymous mutations inMSH2, i.e., V239L and the novel mutations E459K, R847C, Q386K, T772S, and V239/D946E. Functional analysis ofMSH2mutations revealed that 49% of the tested strains (40/81) contained a partial loss-of-functionMSH2mutation. The novelMSH2substitution Q386K produced higher frequencies of CAS-resistant colonies upon expression in themsh2Δmutant. However, expression of two other novelMSH2alleles, i.e., E459K or R847C, did not confer selection of resistant colonies, confirming that not all mutations in theMSH2MMR pathway affect its function or generate a phenotype of resistance to antifungal drugs. The lack of drug resistance prevented any correlations from being drawn with respect toMSH2genotype.

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