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At least 19 recordsLinked to original sources

PubMed2025

Ribose Sugar Alters Conformational Sampling of G⋅T Mismatched Duplex DNA.

Polymerases erroneously incorporate Guanine-Thymine (dG⋅dT) mismatches in genomic DNA that further evades repair by transient sampling of tautomeric/ionic states compromising fidelity of repairing dG⋅dT mismatches. In conjunction, significant frequency of ribose (mis)incorporation in duplex DNA permits for misincorporated-mismatch in the genome. Ribose incorporated G (rG) mismatched with T (rG⋅dT) is the most stable across all misincorporated-mismatch calling into question the conformational consequences of the ribose sugar in addition to the mismatch. In this work, the effects of single rG⋅dT is investigated within a dodecamer DNA duplex employing solution-state NMR spectroscopy, partial anisotropic measurements in conjunction with molecular dynamics simulations to evaluate the impact on base pairs and the overall duplex structure. It is observed that rG⋅dT pairs exhibit enhanced flexibility in both base-pair and sugar dynamics compared to dG⋅dT, and the perturbations are enhanced in comparison to a ribose incorporated adenine-thymine (rA-dT) pair. The structural perturbations compared between rG⋅dT and dG⋅dT provides clues on plausible recognition modes of ribonucleotide excision repair (RER) pathway that looks for misincorporated ribose and mismatch repair (MMR) enzymes that scout for a mismatch.

Ribose↗

PubMed2026

Fluorescent reporter assay reveals ribonucleotides promote mismatch correction in vivo.

Ribonucleotides can serve as a strand discrimination signal in reconstituted in vitro biochemical mismatch repair (MMR) assays, but the influence of ribonucleotides on mismatch correction has not been measured directly in vivo. We have developed a fluorescence-based host cell reactivation assay that reports correction of a mismatch in proximity of a site-specifically incorporated ribonucleotide. A ribonucleotide leads to enhanced mismatch correction. While neither inactivation of a single allele nor knockdown of RNaseH2 is sufficient to suppress ribonucleotide directed MMR, a modest but statistically significant impairment for repair of mismatches in the presence of an embedded ribonucleotide is observed in RNaseH2 knockout cell lines. Reporter plasmids with ribonucleotides located in either the 3' or 5' orientation are robustly repaired in MMR-proficient cells but are weakly repaired in MMR-deficient cells, underscoring their utility as effective MMR reporters. Significant ribonucleotide-enhanced mismatch correction was consistently observed in MMR-deficient cells when the ribonucleotide is in the 3' orientation. The presence of a ribonucleotide led to enhanced MMR even in RNaseH2 knockout cells, suggesting that other enzymes may promote ribonucleotide-directed MMR. Loss of RNaseH2 was not sufficient to confer significant resistance to the alkylating agent, temozolomide, in support of a model in which ribonucleotide-directed repair events make minor contributions to the canonical MMR pathway in mammalian cells. We propose a model in which MMR-independent ribonucleotide enhanced correction of mismatches can proceed by ribonucleotide excision repair when the ribonucleotide is in the 5' direction, and proceeds by an unknown mechanism when the ribonucleotide is in the 3' direction.

DNA Mismatch Repair↗

PubMed2026

The combined impact of HLA and non-HLA mismatch between donors and recipients on kidney transplant survival: a genomic analysis in a prospective cohort.

BACKGROUND: Kidney transplantation outcomes are strongly influenced by immunological compatibility between donor and recipient. While genetic mismatches in the human leukocyte antigen (HLA) region have long been recognised as key determinants of graft survival, increasing evidence, including our own previous work, suggests that non-HLA alloimmunity also plays a critical role. METHODS: We sequenced exomes of deceased kidney donor and recipient pairs in the prospective kidney transplant cohort at the Vienna General Hospital, recruited between January 1, 2012, and June 15, 2023. Out of 1209 pairs, 1187 passed quality control for analysis. Non-HLA mismatch was computed by considering non-synonymous single nucleotide polymorphisms specifically encoding trans-cell membrane or secreted proteins in the kidney (nsSNP-tcmsk). Using adjusted Cox proportional hazards models, we replicated results from our earlier work in recipients with primary graft function after 90 days, and extended the analysis to the combination of nsSNP-tcmsk with eplet mismatch to assess their associations with graft loss in the full cohort. FINDINGS: Of 20,421 human proteins, 2371 were considered for the nsSNP-tcmsk score. In our replication analysis we estimated for nsSNP-tcmsk a hazard ratio (HR) of 1.33 (95% CI 1.02-1.74) for graft loss per increase of one interquartile range. The nsSNP-tcmsk and eplet mismatch were uncorrelated (Spearman correlation coefficient 0.02, p = 0.47). A composite score of nsSNP-tcmsk and eplet mismatch was associated with graft loss with a HR of 1.76 (95% CI 1.20-2.57) corresponding to an absolute difference in 7-year restricted mean survival time between the first and fourth quartiles of 0.52 years (95% CI 0.16-0.87 years). INTERPRETATION: The impact of non-HLA donor-recipient mismatch on transplant loss is of the same magnitude as established mismatch scores in the HLA region. Together, these scores may be further validated as guiding markers for the required strength of maintenance immunosuppression. FUNDING: Vienna Science and Technology Fund, NIH/NIAID.

Humans↗

PubMed1979

Increased binding of ethidium bromide to polynucleotide duplexes containing mismatched bases.

The binding of the intercalating dye ethidium bromide to a series of synthetic polynucleotide duplexes containing varying concentrations of mismatched bases has been measured by fluorescence titration. The dye binds more strongly to duplexes with mismatches, the estimated increase in affinity being twenty-fold for the series of molecules poly (I).poly (C,Ax) with x denoting the mole fraction of mismatched A residues in the C strand. The results are consistent with one requirement of the Streisinger model for frameshift mutagenesis, namely that frameshifting agents can function by stablizing mismatched transient intermediates in DNA.

Base Composition↗

PubMed1977

Mismatch excision and possible polarity effects result in preferred deoxyribonucleic acid strand of integration in pneumococcal transformation.

Heteroduplex deoxyribonucleic acid molecules having a drug resistance marker on one strand and its wild-type allele on the other have been used as donors in pneumococcal transformation. Opposite strands are not equally effective in producing transformants, and this strand bias is not the same, either in direction or magnitude, for various different genetic markers. Selective excision of mismatched base pairs is probably responsible for the large differences in strand efficiency seen with discriminating (hex+) strains, for when the recipient is nondiscriminating (hex-), and therefore presumably lacking an excision enzyme system, strand bias is drastically reduced or altered. The evidence also indicates that excision occurs after integration, as it is provoked by specific donor-recipient mismatch and not by the same mismatch when introduced within donor heteroduplex molecules. Excision can extend to include a neighboring linked marker which would otherwise not be excised, thus altering its intrinsic strand bias as well as its efficiency in transformation. There is a small bias in relative strand efficiency for some markers, not caused by mismatch excision, which perhaps is due to polarity in the integration process itself.

Aminopterin↗

PubMed1978

Bromouracil mutagenesis and mismatch repair in mutator strains of Escherichia coli.

A screening procedure based on the formation of papillae on individual bacterial colonies was used to isolate mutants of Escherichia coli with high mutation rates in the presence of bromouracil. Most of the mutants obtained had high spontaneous mutation rates and mapped close to the previously known mutators mutT, mutS, mutR, uvrE and mutL. Except for mutants of mutT type, these mutators also showed high mutability by bromouracil. Transfection experiments were performed with heteroduplex lambda DNA to test for mismatch repair. The results suggest a reduced efficiency of repair of mismatched bases in mutators mutS, mutR, uvrE and mutL, whereas mutants mapping as mutT appear normal. The results support a connection between spontaneous and bromouracil-induced mutability and repair of mismatched bases in DNA.

Bromouracil↗

PubMedDate not supplied

Afterload mismatch and preload reserve: a conceptual framework for the analysis of ventricular function.

A two-dimensional framework can be used for considering the characteristics of left ventricular ejection in terms of the appropriateness of the matching between afterload and the level of inotropic state, as modulated by the preload reserve. An afterload mismatch (reduced velocity and extent of shortening) can be induced acutely in the normal heart under controlled conditions if the preload is not allowed to compensate for an increased afterload, or if the limit of preload (Frank-Starling) reserve has been reached. In the intact circulation the normal heart is sensitive to some degree to acute changes in afterload, perhaps due to impaired venous return; but under basal resting conditions the ejection phase measures (such as the ejection fraction and the mean velocity of circumferential fiber shortening or VCF, corrected for heart size) encompass a relatively narrow range. This finding, and the lack of change in ejection phase measures after the normal heart has adapted to a chronic pressure or volume overload, provides justification for the use of ejection phase indices for detecting depressed inotropic state under basal conditions. When there is mild depression of myocardial inotropic state, with or without accompanying mechanical overload, enhanced preload may allow full compensation, but acute pressure loading may allow early detection of a less than normal preload reserve. When the inotropic state is substantially reduced, however, a mismatch between afterload and contractility (a reduction in mean VCF) will become evident even in the basal state (venous return being presumed to be adequate under these conditions). The concept of afterload mismatch with limited preload reserve provides an explanation for the value of ejection phase indices compared to isovolunic phase measures in assessing the basal level of inotropic state: the former may be more reliable because they are sensitive to afterload. The effects and implications of therapeutic afterload reduction as modulated by the preload also are understood within this framework.

Animals↗

PubMed1979

Hybridization of synthetic oligodeoxyribonucleotides to phi chi 174 DNA: the effect of single base pair mismatch.

Oligodeoxyribonucleotides complementary to the DNA of the wild type (wt) bacteriophage phi chi 174 have been synthesized by the phosphotriester method. The oligomers, 11, 14, and 17 bases long, are complementary to the region of the DNA which accounts for the am-3 point mutation. When hybridized to am-3 DNA, the oligonucleotides form duplexes with a single base pair mismatch. The thermal stability of the duplexes formed between wt and am-3 DNAs has been measured. The am-3 DNA:oligomer duplexes dissociate at a temperature about 10 degrees C lower than the corresponding wt DNA:oligomer duplexes. This dramatic decrease in thermal stability due to a single mismatch makes it possible to eliminate the formation of the mismatched duplexes by the appropriate choice of hybridization temperature. These results are discussed with respect to the use of oligonucleotides as probes for the isolation of specific cloned DNA sequences.

Bacteriophage phi X 174↗

PubMed2026

Bayesian Integration of Tumor Mutational Signatures and Somatic Features Refines Pathogenicity Assessment of Germline Mismatch Repair Variants.

Variants of uncertain significance (VUS) in mismatch repair (MMR) genes represent a persistent bottleneck in germline interpretation for Lynch syndrome, creating a critical opportunity to leverage tumor biology to refine pathogenicity assessment. Although tumor features such as microsatellite instability (MSI) and immunohistochemistry (IHC) are routinely evaluated, they are typically interpreted separately from germline classification, and their quantitative contribution within ACMG/AMP frameworks remains poorly defined. We therefore analyzed paired germline and tumor sequencing data from 1110 tumors across 1073 patients with colorectal or endometrial cancer to determine whether mismatch repair-deficient (MMR-d) mutational signatures can be quantitatively integrated into Bayesian germline variant interpretation. Using COSMIC single-base substitution signatures, tumors were classified as MMR-d or MMR proficient, and an empirically derived likelihood ratio (LR) quantified the association between MMR-d signatures and pathogenic germline MMR variants. The presence of an MMR-d signature increased the likelihood of an underlying pathogenic germline MMR variant approximately eightfold (LR ≈ 8; log10 LR ≈ 0.90), whereas its absence provided moderate-to-strong benign evidence (LR ≈ 0.156; log10 LR ≈ -0.81). Applying this integrative framework to 45 germline MMR VUS, joint modeling of tumor mutational signatures with additional somatic and variant-level evidence resulted in clinically significant reclassification of 38 (84.4%) variants, including three reclassified as pathogenic or likely pathogenic and 35 as likely benign. A total of 16 downgraded variants were independently downgraded by Invitae. These findings demonstrate that tumor mutational signatures can be formally incorporated into Bayesian germline interpretation, transforming tumor data into quantitative pathogenicity evidence and offering a principled strategy to reduce VUS burden in hereditary cancer genetics.

Humans↗

PubMed1977

Successful transfusion of platelets "mismatched" for HLA antigens to alloimmunized thrombocytopenic patients.

A critical factor limiting the availability of histocompatible platelet transfusions for alloimmunized, thrombocytopenic patients is the large pool of HLA-typed donors needed to procure platelets perfectly matched for HLA antigens. We have, therefore, investigated the effectiveness of platelets obtained from donors having lesser degrees of histocompatibility. In 421 transfusions administered to 59 alloimmunized patients who were refractory to "random donor" platelets, it was found that platelets mismatched for 1 or 2 "cross-reactive" HLA antigens were in most instances as effective in increasing circulating platelet levels as perfectly matched platelets. A significant number of patients also responded to platelets from donors selectively mismatched for non-cross-reactive HLA antigens. The latter group had a significantly reduced frequency of the antigen HLA-A2 (13%) in comparison to the total patient population (49%). Use of donors whose HLA antigens are serologically cross-reactive with those of alloimmunized patients provides approximately 10 times as many prospective donors as does selection based on matching for HLA and simplifies the procurement of hemostatically effective platelets for such patients.

Blood Platelets↗

PubMed1978

The recognition of mismatched base pairs in DNA by DNase I from Ustilago maydis.

The activity of Ustilago maydis DNase I, an enzyme implicated in genetic recombination, on DNA substrates containing unpaired or mismatched bases, was examined. The enzyme nicked supercoiled PM-2 molecules, converting these to relaxed circular and linear molecules. Discrete double stranded linear fragments smaller than unit length were also observed after digestion at high enzyme concentration. Heteroduplex molecules were constructed using phi80 bacteriophage derivatives which contained single base substitutions within the E. coli tRNA1tyr gene. Single and double stranded nicking at or near the single mismatched site was observed with three out of the five pairs of heteroduplexes.

Alleles↗

PubMed1979

Immunoprophylactic anti-Rho(D) treatment after mismatched transfusions.

80 cases of anti-Rho(D) treatment after mismatched transfusions are reviewed to compare the intramuscular (i.m.) and intravenous (i.v.) route of treatment. No severe reactions such as renal failure occurred with either method of anti-D treatment. If the Rh-immune globulin is injected i.m., 20 micrograms anti-D per ml red cells are used. For i.v. anti-D administration, 10-12 micrograms anti-D are suggested. The i.v. method of anti-D treatment is recommended for the future. Furthermore, a scheme of treatment for after mismatched transfusions is described.

Blood Grouping and Crossmatching↗

PubMed2025

Association Between HLA-DRB1 Serotype and HLA-DQB1 Allele Mismatches and Acute Rejection in Kidney Transplantation.

The purpose of this single-center case-control study was to investigate the association between HLA serotype mismatch (MM), compared to other HLA MM modalities, and the occurrence of acute rejection (AR) within the first year after deceased donor kidney transplantation. The study included 198 transplants in 99 pairs of recipients of kidneys from the same donor, where one recipient experienced AR and the other survived the first year without AR. Donors and recipients were typed with NGS for 11 HLA loci at high resolution. HLA MM categories included allele groups, alleles, serotypes, amino acids, EMMA, eplet and PIRCHE-II. Additionally, we investigated Cytomegalovirus LIL peptide (CMV LIL) MM. Recipients with AR presented higher frequencies of pre-transplant HLA-ABDR DSA (20.2% vs. 6.1%, p = 0.005) and CMV LIL MM (24.2% vs. 10.1%, p = 0.01). Univariate and multivariate Cox proportional hazards regression for matched-pair analyses were used to test the association between HLA MM and AR. Univariate analyses indicated significant association with DRB1 ST, HLA-DQB1 AG, HLA-DQB1 AL, EMMA C, EMMA DQB1, Eplet ABC and Eplet DQ MM. Different models were tested in multivariate analyses, all including pre-transplant HLA-ABDR DSA and CMV LIL MM. The models were compared using the Akaike Information Criterion (AIC). The best estimate for AR prediction (AIC = 97.6) was the model that included pre-transplant HLA-ABDR DSA (HR = 11.97; p = 0.003), CMV LIL MM (HR = 367.2; p < 0.001), HLA-DRB1 serotype MM (9.65; p = 0.002) and HLA-DQB1 allele MM (HR = 3.54; p = 0.033). In conclusion, this original report demonstrates an association between the HLA-DRB1 serotype MM and AR, highlighting that serotypes are clinically relevant.

Humans↗

PubMed2026

Uptake of germline testing for Lynch Syndrome in patients with deficient mismatch repair/ microsatellite-high colorectal cancer in the public hospital system in South Australia.

Lynch syndrome (LS) accounts for approximately 4% of colorectal cancer (CRC) cases and arises from pathogenic variants in mismatch repair (MMR) genes. Australian guidelines recommend universal MMR or microsatellite instability (MSI) screening in all CRC patients; however, real-world uptake remains variable. This study evaluated rates of MMR/MSI screening, germline testing, and genetics referrals across two major public hospitals in South Australia. A retrospective review of 1775 patients discussed at colorectal multidisciplinary team meetings in the Royal Adelaide and Queen Elizabeth hospitals between January 2021 and December 2023 was conducted to identify rates of MMR/MSI screening and subsequent referral of eligible patients to genetics. Of the 1129 colorectal cancer cases identified, MMR/MSI testing was performed in 93.2% (1052/1129), with deficiency detected in 12.5% (131/1052). Of these, 37% (49/131) were eligible for genetics referral after exclusion of somatic causes. Among eligible patients, 73.5% (36/49) were referred, and 43% (21/49) underwent germline testing. LS was confirmed in 12 patients (9% of deficient MMR CRC), while 9 patients (6.9%) were classified as having Lynch-like syndrome. Despite high screening rates, gaps remain in genetics referral and testing. Barriers included lack of reflex testing, loss to follow-up, and patient refusal. Targeted system-level interventions and improved genomic education are needed to enhance adherence to guidelines and optimise patient outcomes.

Humans↗

PubMed2026

Primary mismatch repair deficient glioma, IDH-wildtype and H3-wildtype: A giant cell tumor with potential for long-term survival occurring at all ages.

BACKGROUND: Replication repair deficiency is associated with increased risk of developing malignant gliomas. The aim of this study was to investigate primary mismatch repair deficient gliomas (PMMRDGs), a group of IDH-wildtype and H3-wildtype gliomas that is enriched among patients with CMMRD and Lynch syndrome. METHODS: We investigated how PMMRDGs differ from other gliomas with respect to DNA methylation profile, genomic alterations, histopathology, and clinical outcomes. RESULTS: PMMRDGs occur in pediatric, adolescents and the elderly, falling in two related methylation clusters and are characterized by a high frequency of replication repair deficiency. Histology showed multinucleated giant cells, and immunohistochemistry demonstrated loss of MMR protein expression. Survival analysis revealed long-term survival in patients with high mutational burden (>50 mut/Mb) and an intact chromosome 9p region, which was validated in an independent reference cohort. CONCLUSIONS: Overall, our findings indicate that PMMRDGs represent a distinct type of IDH-wildtype gliomas with potential for long-term survival likely driven by immune activation.

Humans↗

PubMed2026

Cooccurrence of Homologous Recombination Deficiency and Mismatch Repair Deficiency in Colorectal Cancer.

Homologous recombination deficiency (HRD) in colorectal cancer (CRC) remains largely unexplored. In contrast, mismatch repair deficiency (dMMR) occurs in ∼15% of patients with CRC. Although HRD and dMMR have historically been regarded as mutually exclusive, emerging evidence suggests that this mutual exclusivity may not be absolute. Here, we conducted a retrospective cohort study utilizing genomic and transcriptomic data to define HRD status in a Chinese dMMR CRC cohort (n = 99). Multiple machine learning approaches were employed to analyze the expression profiles of these tumors and to develop a classifier distinguishing HRD from homologous recombination proficiency (HRP) in dMMR CRCs. In the Chinese dMMR CRC cohort, 66% of tumors were classified as HRD. Compared with the HRP group, the HRD group had a significantly higher tumor mutational burden and better outcomes. The derived expression signature, comprising eight genes, successfully predicted HRD status in dMMR tumors with high accuracy in the training set (AUC = 0.88, Naïve Bayes) and the test set (AUC = 0.87). In this study, a subset of dMMR CRC tumors with co-occurring HRD was identified, which may have potential implications for patient stratification and the application of targeted therapies, such as PARP inhibitors, in this molecular subgroup.

colorectal cancer↗

PubMed2025

Mismatch-introduced crRNA guided PCR-CRISPR/Cas12a platform improves EGFR point mutation detection in single tumor cell.

Dynamic monitoring of epidermal growth factor receptor (EGFR) mutations is essential for the early identification of resistance and treatment adaptation. Single-cell heterogeneity analysis is crucial for precision cancer medicine, yet sensitive and specific detection methods for individual tumor cells remain challenging. Here, we develop a PCR-CRISPR/Cas12a platform enhanced by the incorporation of mismatched base in crRNA at specific site for single-cell point mutation detection. This platform demonstrated high specificity and sensitivity, detecting point mutation at a frequency of 0.1% and in as low as 1.02 ng of genomic DNA, which represents an improvement over the amplification-refractory mutation system PCR (ARMS-PCR). Notably, the accuracy of the platform is highly consistent with next-generation sequencing (NGS), as evidenced by Kappa test values surpassing 0.9. By utilizing a conical-pore membrane with optimized porosity for single circulating tumor cell (CTC) enrichment, our platform enables point mutations detection in individual tumor cells, offering potential enhancements in precision and reliability for EGFR mutation analysis. This novel methodology holds potential for more accurate and personalized cancer treatment strategies.

Humans↗

PubMed2026

Targeting DNA mismatch repair in Huntington's disease.

Somatic expansion of the HTT CAG repeat is a key feature of Huntington's disease (HD) pathogenesis. Mismatch repair (MMR) enzymes drive this process through erroneous DNA repair, with variants in MMR genes modifying the onset and progression of disease features. Cell-type-specific CAG repeat sizing recently confirmed that elevated somatic expansion underlies the selective vulnerability of HD medium spiny neurons, with expansion beyond certain CAG thresholds associated with distinct stages of cellular pathogenesis. In this review, we synthesise insights from post-mortem brain tissue, cell systems, and mouse models, detailing key CAG repeat-length-dependent changes. In addition, we critically evaluate the MMR proteins MSH3, MLH3, and PMS1 as therapeutic targets for slowing somatic expansion and outline key safety considerations for emerging MMR-modulating approaches.

Huntington Disease↗