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PubMed2004

Baseline levels of chromosome instability in the human lymphoblastoid cell TK6.

Induced genomic instability in the human B lymphoblastoid cell line TK6 manifests itself as increases in end-to-end chromosome fusions and non-reciprocal chromosome translocations. It is not associated with elevated frequencies of specific locus mutations or other cytogenetic alterations. Previous studies on a limited number of cells and end-points suggested that induced instability in TK6 mirrors spontaneous instability in terms of the types of alterations observed. In the present study we expanded on our previous analysis to include more cells and more end-points in order to derive a more precise measure of spontaneous instability in TK6 cells. The frequency of normal growth rate thymidine kinase mutants (TK(-/-)), measured in 44 independently isolated clones, was 2.73 +/- 0.78 x 10(-6)/cell, while that for slow growth mutants was 2.39 +/- 0.52 x 10(-6)/cell. These are similar to the frequencies observed for HPRT mutants in primary human cells. There was wide variation in chromatid break frequencies, but the average break frequency, at 0.04+/-0.01 breaks/cell, was only slightly higher than that reported for primary human cells. In contrast, the dicentric frequency of 0.006/cell was more than 10-fold higher for TK6 cells than that reported for normal primary human cells. Furthermore, the dicentrics in TK6 cells are unusual in that they are the result of end-to-end chromosome fusions. TK6 cells also show much higher levels of non-reciprocal chromosome translocations than are usually observed in primary human cells. The results suggest an inherent instability in TK6 cells that differs from what is observed in primary cells in that it affects the frequency of end-to-end chromosome fusions and non-reciprocal chromosome translocations, but not TK gene mutations or other cytogenetic alterations.

B-Lymphocytes↗

PubMed2004

Dnmt1 deficiency leads to enhanced microsatellite instability in mouse embryonic stem cells.

DNA hypomethylation is frequently seen in cancer and imparts genomic instability in mouse models and some tissue culture systems. However, the effects of genomic DNA hypomethylation on mutation rates are still elusive. We have developed a model system to analyze the effects of DNA methyltransferase 1 (Dnmt1) deficiency on DNA mismatch repair (MMR) in mouse embryonic stem (ES) cells. We generated sibling ES cell clones with and without functional Dnmt1 expression, containing a stable reporter gene that allowed us to measure the slippage rate at a mononucleotide repeat. We found that Dnmt1 deficiency led to a 7-fold increase in the microsatellite slippage rate. Interestingly, the region flanking the mononucleotide repeat was unmethylated regardless of Dnmt1 status, suggesting that it is not the local levels of DNA methylation that direct the increase in microsatellite instability (MSI). The enhanced MSI was associated with higher levels of histone H3 acetylation and lower MeCP2 binding at regions near the assayed microsatellite, suggesting that Dnmt1 loss may decrease MMR efficiency by modifying chromatin structure.

Animals↗

PubMed1997

Microsatellite instability in KSHV/HHV-8 positive body-cavity-based lymphoma.

Body-cavity-based lymphoma (BCBL) is a rare non-Hodgkin-'s lymphoma (NHL) type growing in liquid phase in the body cavities. Virtually all BCBL associate with Kaposi's sarcoma-associated herpesvirus/human herpesvirus type-8 infection in the absence of molecular alterations typical of other NHL categories. Microsatellite instability (MSI), a specific variant of genomic instability frequently associated with human cancers, has not been tested in BCBL thus far. In this report, we have analyzed the presence of MSI in the tumor cells of a male patient affected by AIDS-related BCBL. The genomic configuration of 12 distinct microsatellite loci was investigated by polymerase chain reaction amplification of DNA obtained from the patient's tumor cells and from autologous peripheral blood mononuclear cells. MSI was observed at 4/12 microsatellite repeats tested. Absence of the germline allele at one microsatellite locus mapping to chromosome X indicates that, in this BCBL case, MSI represents a clonal genetic lesion affecting virtually all tumor cells. These data suggest that MSI may be potentially involved in the pathogenesis of AIDS-related BCBL.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Analysis of microsatellite instability in sporadic parathyroid adenomas.

Microsatellite instability (MSI) is the form of genomic instability associated with defective DNA mismatch repair (MMR) in human tumorigenesis. Recent reports have suggested a role for MSI in the pathogenesis of sporadic parathyroid adenomas. However, because of their small sample sizes and/or lack of systematic analysis of genome-wide MSI, these studies have not provided conclusive evidence that MMR defects are a common occurrence in parathyroid neoplasia. To further investigate whether MSI plays an important role in parathyroid tumorigenesis, we analyzed 49 sporadic parathyroid adenomas for MSI using a panel of 5 microsatellite DNA markers that has been recommended for sensitive detection of MSI by the NCI Workshop and validated in other tumor types. These microsatellite loci were amplified by PCR using fluorescent-labeled primers from the 49 samples of template tumor DNA and matching normal DNA isolated from the same patients' peripheral blood leukocytes. None of the 49 tumors showed evidence of MSI at any of the analyzed loci of the NCI marker panel. These observations strongly suggest that defective DNA MMR plays a minor role, if any, in the pathogenesis of sporadic parathyroid adenomas.

Adenoma↗

PubMed2006

The offspring of irradiated parents, are they stable?

Mutation induction in directly exposed cells is currently regarded as the main component of the genetic risk of ionising radiation for humans. However, recent studies showing that exposure to ionising radiation results in elevated mutation rates detectable in the non-irradiated progeny of exposed cells challenge the existing paradigm in radiation biology. This review describes some recent data on radiation-induced genomic instability in vitro and mainly focuses on the in vivo phenomenon of transgenerational instability, where elevated mutation rates are detected in the non-exposed offspring of irradiated parents. The possible mechanisms and implications of transgenerational instability are also discussed.

Animals↗

PubMed2006

Cotranscriptional processes and their influence on genome stability.

Numerous studies support the idea that the complex process of gene expression is composed of multiple highly coordinated and integrated steps. While such an extensive coupling ensures the efficiency and accuracy of each step during the gene expression pathway, recent studies have suggested an evolutionarily conserved function for cotranscriptional processes in the maintenance of genome stability. Specifically, such processes prevent a detrimental effect of nascent transcripts on the integrity of the genome. Here we describe studies indicating that nascent transcripts can rehybridize with template DNA, and that this can lead to DNA strand breaks and rearrangements. We present an overview of the diverse mechanisms that different species employ to keep nascent RNA away from DNA during transcription. We also discuss possible mechanisms by which nascent transcripts impact genome stability, as well as the possibility that transcription-induced genomic instability may contribute to disease.

Biological Evolution↗

PubMedDate not supplied

Differential induction and activation of NF-kappaB transcription complexes in radiation-induced chromosomally unstable cell lines.

Radiation-induced genomic instability is a delayed effect of ionizing radiation that may contribute to radiation carcinogenesis. Prior microarray studies investigating gene expression changes in genomically unstable cell lines isolated after radiation exposure uncovered the differential expression of the NF-kappaB p105 mRNA. In this study, the functionality of the NF-kappaB pathway was examined to determine its role in regulating gene expression changes after oxidative stress in chromosomally stable and unstable human-hamster hybrid clones. Basal DNA-binding activity assays showed no significant differences between the clones; however, further experiments established differences in NF-kappaB induction in three chromosomally unstable clones after acute hydrogen peroxide treatment. A second assay was used to confirm this differential activity in the chromosomally unstable clones by studying reporter gene activation after treatment with hydrogen peroxide. Yet an initial upstream analysis of the pathway revealed no significant increase in the level of IkappaBalpha inhibitor protein in the unstable clones. Downstream tests analyzing the induction of the antiapoptotic target protein Bcl-2 found variable induction among the stable and unstable clones. These differences did not translate to a reduction in clonogenic survival after acute exposure to oxidative stress, as the irradiated but chromosomally stable clone displayed the most sensitivity. Due to its role in regulating a diverse set of cellular functions, including responses to oxidative stress, alterations in the NF-kappaB pathway in chromosomally unstable clones may regulate the differential physiology of a subset of chromosomally unstable clones and could contribute to the perpetuation of the phenotype. However, a specific role for defective induction and activation of this pathway remains unidentified.

Analysis of Variance↗

PubMed2005

Yeast Nhp6A/B and mammalian Hmgb1 facilitate the maintenance of genome stability.

Saccharomyces cerevisiae Nhp6A and Nhp6B are chromatin architectural factors that belong to the high-mobility group box (HMGB) superfamily and appear to be functionally related to mammalian Hmgb1. They bind to the minor groove of double-stranded DNA in a non-sequence-specific manner and thereby influence chromatin structure. Previous work has implicated these proteins in a variety of nuclear processes, including chromatin remodeling, DNA replication, transcription, and recombination . Here, we show that Nhp6A/B loss leads to increased genomic instability, hypersensitivity to DNA-damaging agents, and shortened yeast cell life span that is associated with elevated levels of extrachromosomal rDNA circles. Furthermore, we show that hypersensitivity toward UV light does not appear to reflect a decreased capacity for DNA repair but instead correlates with higher levels of UV-induced thymine dimer adducts being formed in cells lacking Nhp6A/B. Likewise, we show that mouse fibroblasts lacking Hmgb1 display higher rates of damage after UV irradiation than wild-type controls and also exhibit pronounced chromosomal instability. Taken together, these data indicate that Nhp6A/B and Hmgb1 protect DNA from damaging agents and thus guard against the generation of genomic aberrations.

Animals↗

PubMed2004

Werner syndrome protein, the MRE11 complex and ATR: menage-à-trois in guarding genome stability during DNA replication?

The correct execution of the DNA replication process is crucially import for the maintenance of genome integrity of the cell. Several types of sources, both endogenous and exogenous, can give rise to DNA damage leading to the DNA replication fork arrest. The processes by which replication blockage is sensed by checkpoint sensors and how the pathway leading to resolution of stalled forks is activated are still not completely understood. However, recent emerging evidence suggests that one candidate for a sensor of replication stress is ATR and that, together with a member of RecQ family helicases, Werner syndrome protein (WRN) and MRE11 complex, can collaborate to promote the restarting of DNA synthesis through the resolution of stalled replication forks. Here, we discuss how WRN, the MRE11 complex and the ATR kinase could work together in response to replication blockage to avoid DNA replication fork collapse and genome instability.

DNA Damage↗

PubMed2006

BRCA2 in mitotic exit: a new role in regulating genomic stability.

Evaluation of: Daniels MJ, Wang Y, Lee M, Venkitaraman AR: Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science 306, 876-879 (2004). Cytokinesis is the division of the cytoplasm of a parent cell into daughter cells after nuclear division. Cytokinesis failure is often accompanied by the generation of cells with an unstable tetraploidy content, which predisposes the cells to develop aneuploidy and malignancies. A recent study by Venkitaraman's group demonstrates that BRCA2, a breast cancer susceptibility gene product, also functions in mediating normal cytokinesis. Similar to the subcellular localization of Aurora kinase, BRCA2 is present at the cleavage furrow and the midbody during late mitosis. Deficiency in BRCA2 function results in cytokinesis failure, which is associated with abnormal localization of myosin II, a key protein essential for the formation of the cleavage furrow. This study is of significance as it shows for the first time that BRCA2 has a function in controlling mitotic exit, deregulation of which contributes to gross genomic instabilities in daughter cells.

Animals↗

PubMed1997

Microsatellite instability in sporadic mucinous colorectal carcinomas: relationship to clinico-pathological variables.

A series of 44 sporadic mucinous colorectal carcinomas was analysed for microsatellite instability; 30 consecutive sporadic non-mucinous colorectal cancers served as controls. Mucinous carcinomas showed microsatellite instability more frequently than non-mucinous cancers: 26/44 and 8/30, respectively (P = 0.005); the difference was higher for cancers with two or more microsatellite alterations: 12 of the 44 mucinous carcinomas versus one of the 30 non-mucinous carcinomas (P = 0.007). On comparing the clinico-pathological features of mucinous carcinomas with and without microsatellite instabilities, no differences were found with respect to the following variables; sex ratio, tumour localization, tumour size, peritumoural lymphocytic infiltration, Crohn's-like lymphoid reaction, peritumoural fibrosis, Dukes' stage, and relationship with adenoma. Mucinous cancers with DNA replication errors were characterized by three features: onset in younger patients (P < 0.05); exophytic gross shape (P = 0.03); and an expanding pattern of growth (P = 0.003). Of the 12 mucinous carcinomas with instability in two or more microsatellites, ten (83.3 per cent) exhibited an expanding pattern of growth, while mucinous cancers with instability in one microsatellite or without genomic instability showed no distinctive growth pattern. This study confirms the relationship between microsatellite instabilities and mucin production in colorectal carcinomas, but shows that replication error RER-positive and RER-negative mucinous cancers differ in few clinico-pathological features. These differences are only in part similar to those previously reported in RER-positive colorectal carcinomas. These data indicate that mucinous carcinoma of the large bowel could represent a histological subset separate from other histotypes.

Adenocarcinoma, Mucinous↗

PubMed2002

Microsatellite instability is not a common feature in medullary breast cancer.

Microsatellite instability (MSI) is a form of genomic instability associated with defective DNA mismatch repair in tumors. MSI is found in 85-90% of hereditary nonpolyposis colorectal cancer cases; however, its occurrence in breast carcinogenesis still remains to be clarified. In addition, data are limited on the incidence of MSI in the medullary subtype. The purpose of this study was to investigate the occurrence of MSI in medullary breast cancer (MBC). The study included a total of 16 patients with MBC, nine with typical and seven with atypical histology. The incidence of MSI in five microsatellite loci (D2S123, D3S1611, D17S807, D17S796 and Xq11-12) was determined by comparing paired normal and tumor tissue DNA after PCR amplification from paraffin-embedded tissues. All 16 tumors showed stability at five loci. Although the number of microsatellite markers and DNA samples may limit the value of our results, we conclude that the MSI phenotype is uncommon in human MBC.

Journal Article↗

PubMed1998

Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutations similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam criteria.

Muir-Torre syndrome (MTS) is an autosomal dominant disease defined by the coincidence of at least one sebaceous skin tumor and one internal malignancy. About half of MTS patients are affected by colorectal cancer. In a subgroup of MTS patients the disease has an underlying DNA mismatch-repair (MMR) defect and thus is allelic to hereditary nonpolyposis colorectal cancer (HNPCC). The purpose of this study was to examine to what extent germ-line mutations in DNA MMR genes are the underlying cause of the MTS phenotype. We ascertained 16 MTS patients with sebaceous skin tumors and colorectal cancer, and we examined their skin and visceral tumors for microsatellite instability. All the patients exhibited high genomic instability in at least one tumor. The search for germ-line mutations in the hMSH2 and hMLH1 genes in 13 of the MTS patients revealed truncating mutations in 9 (69%): eight mutations in the hMSH2 gene and one in the hMLH1 gene. This is the first systematic search for germ-line mutations in patients ascertained on the basis of sebaceous skin tumors. Our results indicate that (1) MTS patients exhibit significantly more mutations in the hMSH2 gene than in the hMLH1 gene; and (2) the subpopulation of MTS patients who are also affected by colorectal cancer, irrespective of family history and age at onset of tumors, may have a likelihood for an underlying DNA MMR defect similar to that for patients with a family history fulfilling the strict clinical criteria for HNPCC.

Adult↗

PubMed1997

The role of size, sequence and haplotype in the stability of FRAXA and FRAXE alleles during transmission.

Factors involved in the stability of trinucleotide repeats during transmission were studied in 139 families in which a full mutation, premutation or intermediate allele at either FRAXA or FRAXE was segregating. The transmission of alleles at FRAXA, FRAXE and four microsatellite loci were recorded for all individuals. Instability within the minimal and common ranges (0-40 repeats for FRAXA, 0-30 repeats for FRAXE) was extremely rare; only one example was observed, an increased in size at FRAXA from 29 to 39 repeats. Four FRAXA and three FRAXE alleles in the intermediate range (41-60) repeats for FRAXA, 31-60 for FRAXE) were unstably transmitted. Instability was more frequent for FRAXA intermediate alleles that had a tract of pure CGG greater than 37 although instability only occurred in two of 13 such transmissions: the changes observed were limited to only one or two repeats. Premutation FRAXA alleles over 100 repeats expanded to a full mutation during female transmission in 100% of cases, in agreement with other published series. There was no clear correlation between haplotype and probability of expansion of FRAXA premutations. Instability at FRAXA or FRAXE was more often observed in conjunction with a second instability at an independent locus suggesting genomic instability as a possible mechanism by which at least some FRAXA and FRAXE mutations arise.

Alleles↗

PubMed1998

Microsatellite instability is infrequent in sporadic adult gliomas.

Microsatellite instability (MSI) is a form of genomic instability in tumors that may reflect mechanisms underlying carcinogenesis. Assessment of MSI in various types of sporadic tumors is therefore relevant to an understanding of molecular pathogenesis. In the case of sporadic adult gliomas, destabilization of mononucleotide, dinucleotide, and longer repeat sequences has been reported in high-grade tumors, though published estimates of the frequency of MSI vary widely. In the present work, we quantitated the frequency of length alterations at three microsatellite loci in 26 glioma/normal tissue pairs and at nine additional loci in 16 of the pairs. We analyzed di- and tetranucleotide markers, including five previously reported to be unstable in gliomas. and examined mostly high-grade tumors, both diploid and aneuploid. A large proportion of the tumor and normal brain specimens had no detectable activity of the DNA repair protein O6-methylguanine-DNA methyltransferase, a prevalent phenotypic trait in these tissues that we thought might be associated with MSI. We observed no length alterations in 222 sequence analyses, and estimate the frequency of MSI in our tumor sample as < 0.45% unstable sequences among all sequences examined, or < 3.9% gliomas with unstable sequences. We conclude that microsatellite length alterations are infrequent in our tumor population, and interpret currently available literature to indicate that the frequency of MSI is low in sporadic adult gliomas.

Adult↗

PubMed2004

Common fragile genes.

Common chromosome fragile sites show susceptibility to DNA damage, leading to alterations that contribute to cancer development. The cloning and characterization of fragile sites have demonstrated that fragile sites are associated with genes that relate to tumorigenesis. Identification of the basis of instability at fragile sites and the related genes provides an entree to understanding of important aspects of chromosomal instability, a prominent feature of neoplastic genomes. FHIT/FRA3B and WWOX/FRA16D, the most sensitive common fragile genes in the human genome, function as tumor suppressor genes. The common features of these two common fragile genes are summarized, and suggest clues to understanding the relation between genomic instability and tumor biology.

Animals↗

PubMed2026

Frequent mutations in the BIRC3 gene promote metastatic potential of nasopharyngeal carcinoma cells through the TRAF2-NF-κB pathway.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer characterized by highly locoregionally invasive behavior attributable to the latent infection with Epstein-Barr virus (EBV) and genomic instability. It is well established that EBV-encoded oncogenic molecules actively contribute to the malignant behavior of NPC cells. However, the mechanism by which aberrant genomic alterations enable NPC cells to become aggressive remains largely unknown. In the present study, whole-exome sequencing (WES) revealed that the gene encoding the baculoviral IAP repeat-containing 3 (BIRC3) protein was frequently mutated in circulating tumor cells (CTCs) but not in paired primary tumor cells from patients with metastatic NPC. A minigene assay indicated that the c.637 A > G mutation disrupted normal mRNA splicing, resulting in the partial deletion of Exons 2 and 3 and altered stability of BIRC3 mRNA. In vitro experiments demonstrated that ectopic expression of the BIRC3c.637A>G mutant enhanced NPC cell invasive properties, including proliferation, resistance to apoptosis, migration, and invasion. Furthermore, overexpression of wild-type BIRC3 promoted invasive characteristics in NPC cells through the TRAF2-NF-κB signaling axis. In summary, BIRC3 acts as a regulator of the malignant features of NPC cells. Frequent BIRC3 mutations in CTCs, such as the c.637 A > G mutation, further enhance the metastatic potential of disseminated NPC cells by inducing aberrant alternative splicing. These findings suggest the therapeutic feasibility of targeting the BIRC3/TRAF2/NF-κB axis in the treatment of NPC.

Humans↗

PubMed2004

Rereplication by depletion of geminin is seen regardless of p53 status and activates a G2/M checkpoint.

Genomic DNA replication is tightly controlled to ensure that DNA replication occurs once per cell cycle; loss of this control leads to genomic instability. Geminin, a DNA replication inhibitor, plays an important role in regulation of DNA replication. To investigate the role of human geminin in the maintenance of genomic stability, we eliminated geminin by RNA interference in human cancer cells. Depletion of geminin led to overreplication and the formation of giant nuclei in cells that had wild-type or mutant p53. We found that overreplication caused by depletion of geminin activated both Chk1 and Chk2, which then phosphorylated Cdc25C on Ser216, resulting in its sequestration outside the nucleus, thus inhibiting cyclin B-Cdc2 activity. This activated G(2)/M checkpoint prevented cells with overreplicated DNA from entering mitosis. Addition of caffeine, UCN-01, or inhibitors of checkpoint pathways or silencing of Chk1 suppressed the accumulation of overreplicated cells and promoted apoptosis. From these results, we conclude that geminin is required for suppressing overreplication in human cells and that a G(2)/M checkpoint restricts the proliferation of cells with overreplicated DNA.

Apoptosis↗