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PubMed2026

Sequencing approaches in hereditary cancer testing: strengths, limitations and future directions.

Over the past three decades, Hereditary Cancer Testing (HCT) has evolved from single gene assays into multigene panel testing (MGPT), which allows for the screening of all known hereditary cancer genes in a single assay. MGPT is currently the standard approach for clinical HCT. However, with decreasing sequencing costs and increased instrument throughput, the scalability of exome sequencing (ES) and genome sequencing (GS) for HCT indications is becoming more viable. These methods provide broader insights into the coding exons and/or the entire genome, respectively. ES/GS data can also be reanalyzed to identify variants in novel genes that were not characterized at the time of initial testing, or to support research efforts aimed at uncovering additional associations between germline variants and cancer predisposition. Additionally, the emerging use of long-read sequencing (LRS) is noteworthy, enabling improved variant detection compared to short-read sequencing, especially for complex/structural variants and variation in difficult-to-sequence or paralogous regions in genes such as PMS2. This has the potential to increase the accuracy of HCT, reduce the turnaround time, find previously unidentifiable cancer risk variants, and ultimately increase the diagnostic yield. This article provides a comprehensive summary of the sequencing approaches used in HCT, discussing their strengths and limitations. We also highlight the added value of complementing DNA-only testing with RNA and tumor sequencing. Furthermore, we explore LRS-based approaches and discuss opportunities for their implementation in routine genetic testing for hereditary cancer.

Humans↗
PubMed2002

Photodynamic therapy of DNA mismatch repair-deficient and -proficient tumour cells.

Loss of DNA mismatch repair is a common finding in hereditary nonpolyposis colon cancer as well as in many types of sporadic human tumours. DNA mismatch repair-deficient cells have been reported to be resistant to many chemotherapeutic agents and to radiotherapy, and to have the potential of rapidly acquiring additional mutations leading to tumour progression. Photodynamic therapy is a new treatment modality using light to activate a photosensitiser that preferentially localises in tumour cells. An oxygen dependent photochemical reaction ensues, resulting in selective tumour necrosis. The effect of loss of DNA mismatch repair activity on the sensitivity to photodynamic therapy was tested using pairs of cell lines proficient or deficient in mismatch repair due to loss of either MLH1 or MSH2 protein function. Cells were incubated with the photosensitiser 5,10,15,20-meta-tetra(hydroxyphenyl)chlorin and exposed to laser light at 652 nm with various optical doses ranging from 0-1 J cm(-2). Cell survival was assessed using the clonogenic assay. Loss of MLH1 or MSH2 function was not associated with resistance to photodynamic therapy. MCF-7 cells repeatedly treated with photodynamic therapy expressed parental levels of MLH1, MSH2, MSH6, and PMS2. DNA mismatch repair-deficient and -proficient cells showed similar subcellular distributions of meta-tetra(hydroxyphenyl)chlorin as analysed by laser scanning and fluorescence microscopy. Therefore, repeated exposure of tumour cells to photodynamic therapy does not seem to result in loss of DNA mismatch repair, and loss of mismatch repair, in turn, does not seem to contribute to resistance to photodynamic therapy. Our results suggest recommending photodynamic therapy as a strategy for circumventing resistance due to loss of DNA mismatch repair.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Very low prevalence of germline MSH6 mutations in hereditary non-polyposis colorectal cancer suspected patients with colorectal cancer without microsatellite instability.

Hereditary non-polyposis colorectal cancer (HNPCC) is caused by mutations in one of the mismatch repair genes MLH1, MSH2, MSH6, or PMS2 and results in high-level microsatellite instability (MSI-high) in tumours of HNPCC patients. The MSI test is considered reliable for indicating mutations in MLH1 and MSH2, but is questioned for MSH6. Germline mutation analysis was performed in 19 patients with an MSI-high tumour and absence of MSH2 and/or MSH6 protein as determined by immunohistochemistry (IHC), without an MLH1 or MSH2 mutation, and in 76 out of 295 patients suspected of HNPCC, with a non-MSI-high colorectal cancer (CRC). All 295 non-MSI-high CRCs were analysed for presence of MSH6 protein by IHC. In 10 patients with an MSI-high tumour without MSH2 and/or MSH6 expression, a pathogenic MSH6 mutation was detected, whereas no pathogenic MSH6 mutation was detected in 76 patients with a non-MSI-high CRC and normal MSH6 protein expression. In none of the 295 CRCs loss of MSH6 protein expression was detected. The prevalence of a germline MSH6 mutation is very low in HNPCC suspected patients with non-MSI-high CRC. Microsatellite instability analysis in CRCs is highly sensitive to select patients for MSH6 germline mutation analysis.

Adult↗
PubMed2006

Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor.

Heterozygous germline mutations in the human mismatch repair (MMR) genes MLH1, PMS2, MSH2 and MSH6 predispose to the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Biallelic mutations in these genes have been reported for a limited number of cases resulting in hematological malignancies, brain tumors and gastrointestinal tumors early in childhood. These tumor phenotypes are frequently associated with café-au-lait spots (CALS), one of the clinical hallmarks of neurofibromatosis type 1 (NF1). We report the first case of compound heterozygosity for two MSH6 mutations resulting in a nonconservative amino-acid change of a conserved residue and in a premature stop codon in a patient who developed rectal and endometrial cancer at ages 19 and 24 years, respectively, and presented few CALS in a single body segment. Immunohistochemistry and Western blotting revealed only residual expression of the MSH6 protein in the normal cells. The disease history resembles the HNPCC phenotype rather than a phenotype associated with biallelic MMR gene mutations. Therefore, we assume that one or both mutations abolish protein function only partially, further supported by the parents, which are both carriers of one of the mutations each, and not affected by the disease at ages 57 and 58 years. Our data suggest considering biallelic mutations in MMR genes for patients who develop HNPCC-associated tumors at an unusually young age of onset, even without hematological or brain malignancies.

Adult↗
PubMed2001

A role for mismatch repair in control of DNA ploidy following DNA damage.

Many reports have shown a link between mismatch repair (MMR) deficiency and loss of normal cell cycle control, particularly loss of G2 arrest. However almost all of these studies utilized transformed cell lines, and thus the involvement of other genes in this phenotype cannot be excluded. We have examined the effects of cisplatin treatment on primary embryo fibroblasts (MEFs) derived from mice in which the MMR gene Msh2 had been inactivated (Msh2(-/-)). This analysis determined that both primary Msh2(-/-) and wild type (WT) fibroblasts exhibited an essentially identical G2 arrest following cisplatin treatment. Similarly, we observed a cisplatin-induced G2 arrest in immortalized MMR deficient (Mlh1(-/-) and Pms2(-/-)) and WT MEFs. p53 deficient primary MEFs (p53(-/-)) exhibited both a clear G2 arrest and an increase in cells with a DNA content of 8N in response to cisplatin. When the Msh2 and p53 defects were combined (p53(-/-)/Msh2(-/-)) the G2 arrest was essentially identical to the p53(-/-) fibroblasts. However, the p53(-/-)/Msh2(-/-) fibroblasts demonstrated a further increase in cells with an 8N DNA content, above that seen in the p53(-/-) fibroblasts. These results suggest that loss of MMR on its own is not enough to overcome G2 arrest following exposure to cisplatin but does play a role in preventing polyploidization, or aberrant DNA reduplication, in the absence of functional p53.

Animals↗
PubMed2001

Functional analysis of the mismatch repair system in bladder cancer.

In bladder cancer the observed microsatellite instability indicates that mismatch repair deficiency could be a frequently involved factor in bladder cancer progression. To investigate this hypothesis we analysed extracts of seven bladder cancer cell lines and, as a novel approach, five clinical cancer samples for mismatch repair activity. We found that one cell line (T24) and three of the clinical samples had a reduced repair capacity, measured to approximately 20% or less. The T24 cell extract was unable to repair a G-G mismatch and showed reduced repair of a 2-base loop, consistent with diminished function of the MSH2-MSH6 heterodimer. The functional assay was combined with measurement for mutation frequency, microsatellite analysis, sequencing, MTT assay, immunohistochemical analysis and RT-PCR analysis of the mismatch repair genes MSH2, MSH3, MSH6, PMS1, PMS2 and MLH1. A >7-fold relative increase in mutation frequency was observed for T24 compared to a bladder cancer cell line with a fully functional mismatch repair system. Neither microsatellite instability, loss of repair nor mismatch repair gene mutations were detected. However, RT-PCR analysis of mRNA levels did detect changes in the ratio of expression of the Mut S and Mut L homologues. The T24 cell line had the lowest MSH6 expression level of the cell lines tested. Identical RT-PCR analysis of seventeen clinical samples (normal urothelium, 7; pTa low stage, 5; and pT1-4 high stage, 5) indicated a significant change in the expression ratio between MSH3/MSH6 (P< 0.004), MSH2/MSH3 (P< 0.012) and PMS2/MLH1 P< 0.005, in high stage bladder tumours compared to normal urothelium and low stage tumours. Collectively, the data suggest that imbalanced expression of mismatch repair genes could lead to partial loss of mismatch repair activity that is associated with invasive bladder cancer.

Base Pair Mismatch↗
PubMed1998

Clinical findings with implications for genetic testing in families with clustering of colorectal cancer.

BACKGROUND: Germ-line mutations in DNA mismatch-repair genes (MSH2, MLH1, PMS1, PMS2, and MSH6) cause susceptibility to hereditary nonpolyposis colorectal cancer. We assessed the prevalence of MSH2 and MLH1 mutations in families suspected of having hereditary nonpolyposis colorectal cancer and evaluated whether clinical findings can predict the outcome of genetic testing. METHODS: We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familial clustering of colorectal cancer or other cancers associated with hereditary nonpolyposis colorectal cancer. Information on the site of cancer, the age at diagnosis, and the number of affected family members was obtained from all families. RESULTS: Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent). Clinical factors associated with these mutations were early age at diagnosis of colorectal cancer, the occurrence in the kindred of endometrial cancer or tumors of the small intestine, a higher number of family members with colorectal or endometrial cancer, the presence of multiple colorectal cancers or both colorectal and endometrial cancers in a single family member, and fulfillment of the Amsterdam criteria for the diagnosis of hereditary nonpolyposis colorectal cancer (at least three family members in two or more successive generations must have colorectal cancer, one of whom is a first-degree relative of the other two; cancer must be diagnosed before the age of 50 in at least one family member; and familial adenomatous polyposis must be ruled out). Multivariate analysis showed that a younger age at diagnosis of colorectal cancer, fulfillment of the Amsterdam criteria, and the presence of endometrial cancer in the kindred were independent predictors of germ-line mutations of MSH2 or MLH1. These results were used to devise a logistic model for estimating the likelihood of a mutation in MSH2 and MLH1. CONCLUSIONS: Assessment of clinical findings can improve the rate of detection of mutations of DNA mismatch-repair genes in families suspected of having hereditary nonpolyposis colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Repair of large insertion/deletion heterologies in human nuclear extracts is directed by a 5' single-strand break and is independent of the mismatch repair system.

The repair of 12-, 27-, 62-, and 216-nucleotide unpaired insertion/deletion heterologies has been demonstrated in nuclear extracts of human cells. When present in covalently closed circular heteroduplexes or heteroduplexes containing a single-strand break 3' to the heterology, such structures are subject to a low level repair reaction that occurs with little strand bias. However, the presence of a single-strand break 5' to the insertion/deletion heterology greatly increases the efficiency of rectification and directs repair to the incised DNA strand. Because nick direction of repair is independent of the strand in which a particular heterology is placed, the observed strand bias is not due to asymmetry imposed on the heteroduplex by the extrahelical DNA segment. Strand-specific repair by this system requires ATP and the four dNTPs and is inhibited by aphidicolin. Repair is independent of the mismatch repair proteins MSH2, MSH6, MLH1, and PMS2 and occurs by a mechanism that is distinct from that of the conventional mismatch repair system. Large heterology repair in nuclear extracts of human cells is also independent of the XPF gene product, and extracts of Chinese hamster ovary cells deficient in the ERCC1 and ERCC4 gene products also support the reaction.

Base Pair Mismatch↗
PubMed2005

Deletions account for 17% of pathogenic germline alterations in MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer (HNPCC) families.

Hereditary nonpolyposis colorectal cancer (HNPCC) is due to defects in DNA mismatch repair (MMR) genes MSH2, MLH1, MSH6, and to a lesser extent PMS2. Of 466 suspected HNPCC families, we defined 54 index patients with either tumors of high microsatellite instability (MSI-H) and/or loss of expression for either MLH1, MSH2, and/or MSH6, but without a detectable pathogenic point mutation in these genes. This study cohort was augmented to 64 patients by 10 mutation-negative index patients from Amsterdam families where no tumors were available. Deletion/duplication screening using the multiplex ligation-dependent probe amplification (MLPA) revealed 12 deletions in MSH2 and two deletions in MLH1. These deletions constitute 17% of pathogenic germline alterations but elucidate the susceptibility to HNPCC in only 22% of the mutation-negative study cohort, pointing towards other mutation mechanisms for an inherited inactivation of MLH1 or MSH2. We describe here four novel deletions. One novel and one known type of deletion were found for three and two unrelated families, respectively. MLPA analysis proved a reliable method for the detection of genomic deletions in MLH1 and MSH2; however, sequence variations in the ligation-probe binding site can mimic single exon deletions.

Alu Elements↗
PubMed2003

Assessment of mismatch repair function in leukaemic cell lines and blasts from children with acute lymphoblastic leukaemia.

Defects in the DNA mismatch repair (MMR) pathway have recently been shown to be associated with resistance to several of the cytotoxic drugs used in the treatment of children with acute lymphoblastic leukaemia (ALL). We have assessed the MMR status of a range of leukaemic cell lines using an in vitro repair assay and correlated this with protein expression of the best characterized components of the system. We have also assessed MMR in leukaemic blasts from a limited panel of children with ALL and related this to Ki67 expression as a measure of proliferative capacity. Out of nine leukaemic cell lines tested, five of the seven lymphoid lines showed little or no repair using the in vitro assay and had low MMR protein expression. In three (NALM-6, Reh and MOLT 4) MMR defects have not been previously reported. Immunohistochemistry of clinical samples showed a wide range of expression of MLH1, MSH2 and Ki67 in nine cases studied at presentation, with a highly statistically significant correlation between MLH1 and Ki67 expression (r(2) = 0.96, P < 0.0001, Pearson correlation). Western blotting demonstrated high expression of MLH1, PMS2, MSH2 and MSH6 proteins. In vitro analysis of G.T repair using lymphoblast cytosol from the same patients showed a wide range of proficiency, which was markedly reduced in one case studied at relapse. These results suggest that MMR defects are more common in leukaemic cell lines and acute lymphoblastic leukaemias than previously thought.

Adolescent↗
PubMed2000

Efficient repair of A/C mismatches in mouse cells deficient in long-patch mismatch repair.

A previously unrecognized mismatch repair activity is described. Extracts of immortalized MSH2-deficient mouse fibroblasts did not correct most single base mispairs. The same extracts carried out efficient repair of A/C mismatches. A/G mispairs were less efficiently corrected and there was no significant repair of A/A. MLH1-defective mouse extracts also repaired an A/C mispair. A/C correction by Msh2(-/-) mouse cell extracts was not affected by antibodies against the PMS2 protein, which inhibited long-patch mismatch repair. A/C repair activity is thus independent of MutSalpha, MutSbeta and MutLalpha. A/C mismatches were corrected 5-fold more efficiently by extracts of Msh2 knockout mouse cells than by comparable extracts prepared from hMSH2- or hMLH1-deficient human cells. MSH2-independent A/C correction by mouse cell extracts did not require a nick in the circular duplex DNA substrate. Repair involved replacement of the A and was associated with the resynthesis of a limited stretch of </=25 bases of DNA.

Adaptor Proteins, Signal Transducing↗
PubMed2005

PCNA-MutSalpha-mediated binding of MutLalpha to replicative DNA with mismatched bases to induce apoptosis in human cells.

Modified bases, such as O6-methylguanines, are produced in cells exposed to alkylating agents and cause apoptosis. In human cells treated with N-methyl-N-nitrosourea, we detected a protein complex composed of MutSalpha, MutLalpha and PCNA on damaged DNA by immunoprecipitation method using chromatin extracts, in which protein-protein interactions were stabilized by chemical crosslinking. Time course experiments revealed that MutSalpha, consisting of MSH2 and MSH6 proteins, and PCNA bind to DNA to form an initial complex, and MutLalpha, composed of MLH1 and PMS2, binds to the complex when the DNA is damaged. This sequential mode of binding was further confirmed by the findings that the association of PCNA-MutSalpha complex on chromatin was observed even in the cells that lack MLH1, whereas in the absence of MSH2 no association of MutLalpha with the chromatin was achieved. Moreover, reduction in the PCNA content by small-interfering RNA or inhibition of DNA replication by aphidicolin, an inhibitor of DNA polymerase, significantly reduced the levels of the PCNA-MutSalpha-MutLalpha complex and also suppressed an increase in the caspase-3 activity, a hallmark for the induction of apoptosis. These observations imply that the induction of apoptosis is coupled with the progression of DNA replication through the action of PCNA.

Apoptosis↗
PubMed2006

Mutations in the MutSalpha interaction interface of MLH1 can abolish DNA mismatch repair.

MutLalpha, a heterodimer of MLH1 and PMS2, plays a central role in human DNA mismatch repair. It interacts ATP-dependently with the mismatch detector MutSalpha and assembles and controls further repair enzymes. We tested if the interaction of MutLalpha with DNA-bound MutSalpha is impaired by cancer-associated mutations in MLH1, and identified one mutation (Ala128Pro) which abolished interaction as well as mismatch repair activity. Further examinations revealed three more residues whose mutation interfered with interaction. Homology modelling of MLH1 showed that all residues clustered in a small accessible surface patch, suggesting that the major interaction interface of MutLalpha for MutSalpha is located on the edge of an extensive beta-sheet that backs the MLH1 ATP binding pocket. Bioinformatic analysis confirmed that this patch corresponds to a conserved potential protein-protein interaction interface which is present in both human MLH1 and its E.coli homologue MutL. MutL could be site-specifically crosslinked to MutS from this patch, confirming that the bacterial MutL-MutS complex is established by the corresponding interface in MutL. This is the first study that identifies the conserved major MutLalpha-MutSalpha interaction interface in MLH1 and demonstrates that mutations in this interface can affect interaction and mismatch repair, and thereby can also contribute to cancer development.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Dysregulation of DNA repair pathways in a transforming growth factor alpha/c-myc transgenic mouse model of accelerated hepatocarcinogenesis.

Previous work from our laboratory has implicated oxidative DNA damage and genetic instability in the etiology of transforming growth factor-alpha (TGFalpha)/c-myc-associated hepatocarcinogenesis. In contrast, oxidative DNA damage was lower in c-myc single-transgenic mice, consistent with less chromosomal damage and with later and more benign tumor formation. We examined whether defects in the DNA repair pathways contribute to the acceleration of liver cancer in TGFalpha/c-myc mice. A cDNA expression array containing 140 known genes and multiplex RT-PCR were used to compare the basal levels of expression of DNA repair genes at the dysplastic stage. Thirty-five percent (8/23) and 43% (10/23) of DNA repair genes were constitutively up-regulated in 10-week-old TGFalpha/c-myc and c-myc transgenic livers, respectively, compared with wild-type controls. The commonly up-regulated genes were OGG1 and NTH1 of base excision repair; ERCC5, RAD23A, and RAD23B of nucleotide excision repair; and RAD50, RAD52, and RAD54 involved in DNA strand break repair. Additional treatment with a peroxisome proliferator, Wy-14,643, known to increase the level of oxidants in the liver, failed to induce a further increase in the expression level of DNA repair enzymes in TGFalpha/c-myc but not in c-myc or wild-type livers. Moreover, expression of several genes, including Ku80, PMS2, and ATM, was decreased in TGFalpha/c-myc livers, suggesting a fault or inefficient activation of the DNA repair pathway upon induction of oxidative stress. Together, the results show that DNA damage response is attenuated in TGFalpha/c-myc mice, creating a condition that may contribute to acceleration of liver cancer in this model.

Animals↗
PubMed2006

Chromosomal and microsatellite instability of adenocarcinomas and dysplastic lesions (DALM) in ulcerative colitis.

Longstanding ulcerative colitis (UC) is associated with a high risk of developing UC-related colonic adenocarcinoma (UCC). These carcinomas originate from nonadenomatous dysplastic regions referred to as dysplasia associated lesion or mass (DALM). We evaluated chromosomal and microsatellite instability (MSI) in 21 DALM/UCCs. Chromosomal instability was determined by high-resolution array comparative genomic hybridization with a 3500-element BAC-PAC array. MSI was assessed with markers BAT25 and BAT26 and by immunohistochemical analysis of mismatch repair genes. Comparative genomic hybridization revealed frequent losses of array clones (>20% of tumors) at chromosome arms 4p, 5q, and 18q, frequent gains of array clones (>20% of tumors) were found at 1q, 5p, 6p, 7p, 7q, 8p, 8q, 11p, 11q, 12q, 14q, 17q, 19q, 20p, and 20q. The pattern of alterations is dominated by gains on 5p and 20q with loss of 4p, all of which were already present in a patient with carcinoma in situ. Immunohistochemical analysis of mismatch repair genes MLH1, PMS2, MSH2, and MSH6 showed negative immunostaining in 1 neoplasm (5%). MSI of BAT25 and BAT26 was seen in 3 tumors (14%) including the neoplasm with aberrant immunostaining. In conclusion, we constructed a genomic profile of DALM/UCC including several novel genetic alterations. Further, we found a low percentage of MSI. Thus, DALM/UCCs display profound chromosomal instability, but this is not associated with concurrent MSI.

Adenocarcinoma↗
PubMed2026

NTRK-positive collision tumor of the gastrointestinal tract: a rare entity case report.

Neurotrophic receptor tyrosine kinase (NTRK) fusion-positive colorectal cancer (CRC) represents a rare molecular subset of CRC. We report an exceptional case of a collision tumor composed of two anatomically adjacent but histologically and genomically distinct primary colorectal carcinomas, each giving rise to a corresponding metastasis. Comprehensive histopathologic and molecular analyses demonstrated that one primary tumor and its matched metastasis consisted predominantly (>&#xa0;90%) of a solid carcinoma harboring a TPR::NTRK fusion, high microsatellite instability (MSI-H), elevated tumor mutational burden (TMB), and loss of MLH1 and PMS2 expression by immunohistochemistry. In contrast, the second primary tumor and its corresponding metastasis exhibited conventional adenocarcinoma morphology with mucinous differentiation, lacked an NTRK fusion, and carried canonical driver mutations in KRAS, APC, SMAD4, and TP53. This case underscores the importance of integrated histopathologic and molecular evaluation in CRCs with heterogeneous morphology, as the identification of multiple, genomically distinct tumor components may have significant diagnostic, prognostic, and therapeutic implications.

NTRK gene fusion↗
PubMed2025

RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.

TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to the formation of detrimental cytosolic aggregates and a reduction in nuclear functionality within neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expressions. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.

Amyotrophic lateral sclerosis↗
PubMed1989

Heteroduplex DNA correction in Saccharomyces cerevisiae is mismatch specific and requires functional PMS genes.

In vitro-constructed heteroduplex DNAs with defined mismatches were corrected in Saccharomyces cerevisiae cells with efficiencies that were dependent on the mismatch. Single-nucleotide loops were repaired very efficiently; the base/base mismatches G/T, A/C, G/G, A/G, G/A, A/A, T/T, T/C, and C/T were repaired with a high to intermediate efficiency. The mismatch C/C and a 38-nucleotide loop were corrected with low efficiency. This substrate specificity pattern resembles that found in Escherichia coli and Streptococcus pneumoniae, suggesting an evolutionary relationship of DNA mismatch repair in pro- and eucaryotes. Repair of the listed mismatches was severely impaired in the putative S. cerevisiae DNA mismatch repair mutants pms1 and pms2. Low-efficiency repair also characterized pms3 strains, except that correction of single-nucleotide loops occurred with an efficiency close to that of PMS wild-type strains. A close correlation was found between the repair efficiencies determined in this study and the observed postmeiotic segregation frequencies of alleles with known DNA sequence. This suggests an involvement of DNA mismatch repair in recombination and gene conversion in S. cerevisiae.

Alleles↗