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PubMed2025

A transient mutational burst occurs during yeast colony development.

Characterizing the contribution of mutators to mutation accumulation is essential for understanding cellular adaptation and diseases like cancer. By measuring single and double mutation rates, including point mutations, segmental duplications, and reciprocal translocations, we found that wild-type yeast colonies exhibit double mutation rates up to 17 times higher than expected from experimentally determined single mutation rates. These double mutants retained wild-type mutation rates, indicating they originated from genetically normal cells that transiently expressed a mutator phenotype. Numerical simulations suggest that transient mutator subpopulations likely consist of less than a few thousand cells, and experience high-intensity mutational bursts for less than five generations. Most double mutations accumulated sequentially across cell cycles, with simultaneous acquisition being rare and likely linked to systemic genomic instability. Additionally, we explored the genetic control of transient hypermutation and found that the excess of double mutants can be modulated by replication stress and the DNA damage tolerance pathway. Our findings suggest that transient mutators play a significant role in genomic instability and contribute to the mutational load accumulating in growing isogenic populations.

Saccharomyces cerevisiae↗
PubMed2003

Hyperproliferation and p53 status of lens epithelial cells derived from alphaB-crystallin knockout mice.

alphaB-Crystallin, a major protein of lens fiber cells, is a stress-induced chaperone expressed at low levels in the lens epithelium and numerous other tissues, and its expression is enhanced in certain pathological conditions. However, the function of alphaB in these tissues is not known. Lenses of alphaB-/- mice develop degeneration of specific skeletal muscles but do not develop cataracts. Recent work in our laboratory indicates that primary cultures of alphaB-/- lens epithelial cells demonstrate genomic instability and undergo hyperproliferation at a frequency 4 orders of magnitude greater than that predicted by spontaneous immortalization of rodent cells. We now demonstrate that the hyperproliferative alphaB-/- lens epithelial cells undergo phenotypic changes that include the appearance of the p53 protein as shown by immunoblot analysis. Sequence analysis showed a lack of mutations in the p53 coding region of hyperproliferative alphaB-/- cells. However, the reentry of hyperproliferative alphaB-/- cells into S phase and mitosis after DNA damage by gamma-irradiation were consistent with impaired p53 checkpoint function in these cells. The results demonstrate that expression of functionally impaired p53 is one of the factors that promote immortalization of lens epithelial cells derived from alphaB-/- mice. Fluorescence in situ hybridization using probes prepared from centromere-specific mouse P1 clones of chromosomes 1 and 9 demonstrated that the hyperproliferative alphaB-/- cells were 30% diploid and 70% tetraploid, whereas wild type cells were 83% diploid. Further evidence of genomic instability was obtained when the hyperproliferative alphaB-/- cells were labeled with anti-beta-tubulin antibodies. Examination of the hyperproliferative alphaB-/- mitotic profiles revealed the presence of cells that failed to round up for mitosis, or arrested in cytokinesis, and binucleated cells in which nuclear division had occurred without cell division. These results suggest that the stress protein and molecular chaperone alphaB-crystallin protects cells from acquiring impaired p53 protein and genomic instability.

Animals↗
PubMed2006

Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity.

The ubiquity of mobile elements in mammalian genomes poses considerable challenges for the maintenance of genome integrity. The predisposition of mobile elements towards participation in genomic rearrangements is largely a consequence of their interspersed homologous nature. As tracts of nonallelic sequence homology, they have the potential to interact in a disruptive manner during both meiotic recombination and DNA repair processes, resulting in genomic alterations ranging from deletions and duplications to large-scale chromosomal rearrangements. Although the deleterious effects of transposable element (TE) insertion events have been extensively documented, it is arguably through post-insertion genomic instability that they pose the greatest hazard to their host genomes. Despite the periodic generation of important evolutionary innovations, genomic alterations involving TE sequences are far more frequently neutral or deleterious in nature. The potentially negative consequences of this instability are perhaps best illustrated by the >25 human genetic diseases that are attributable to TE-mediated rearrangements. Some of these rearrangements, such as those involving the MLL locus in leukemia and the LDL receptor in familial hypercholesterolemia, represent recurrent mutations that have independently arisen multiple times in human populations. While TE-instability has been a potent force in shaping eukaryotic genomes and a significant source of genetic disease, much concerning the mechanisms governing the frequency and variety of these events remains to be clarified. Here we survey the current state of knowledge regarding the mechanisms underlying mobile element-based genetic instability in mammals. Compared to simpler eukaryotic systems, mammalian cells appear to have several modifications to their DNA-repair ensemble that allow them to better cope with the large amount of interspersed homology that has been generated by TEs. In addition to the disruptive potential of nonallelic sequence homology, we also consider recent evidence suggesting that the endonuclease products of TEs may also play a key role in instigating mammalian genomic instability.

Animals↗
PubMed1998

Microsatellite analysis in childhood acute lymphoblastic leukemia.

BACKGROUND AND OBJECTIVE: Genetic alterations, including genomic instability, represent possible steps towards a malignant transformation. One approach to delineate replication errors in cancer cells is to determine alterations of microsatellites that are short tandem repeat sequences dispersed throughout the human genome. We have investigated whether genomic instability may be a possible event in the leukemogenic process by evaluating the pattern of instability in 41 cases of childhood acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Eighty-two samples of genomic DNA (41 at diagnosis and 41 at remission) were analyzed by PCR with microsatellite markers chosen on five different chromosomes (2, 10, 11, 13, 18) known to be frequently involved in tumors of various origins. Since deletions of the short arm of chromosome 12 are relatively common in children with ALL, we also analyzed one region flanked by the microsatellite marker D12S308 on 12p. This area encompasses a genetic locus which contains the putative suppressor gene KIP1. RESULTS: A pattern of MI at one or two loci on different chromosomes could be documented in 4 of the 41 cases analyzed (9.7%). Three were common ALL and 1 was a T-ALL. One case showed two concomitant sites of instability, while 1 revealed two additional bands by using simultaneously microsatellite markers D2S123 and D18S58. INTERPRETATION AND CONCLUSIONS: These results indicate that genetic instability of microsatellite repeat sequences occurs in a proportion of childhood ALL. Mismatched repair errors documented in hereditary and sporadic solid tumors may thus be involved in hematological malignancies. While in such cases the pattern of genomic instability appears indicative of a mutator phenotype and of a potential predisposition towards a leukemic transformation, other genomic loci close to cytogenetic and molecular alterations known to occur in ALL need to be investigated in depth in cases with an apparently non mutated phenotype.

Child↗
PubMed2004

Damaging and protective cell signalling in the untargeted effects of ionizing radiation.

The major adverse consequences of radiation exposures are attributed to DNA damage in irradiated cells that has not been correctly restored by metabolic repair processes. However, the dogma that genetic alterations are restricted to directly irradiated cells has been challenged by observations in which effects of ionizing radiation arise in non-irradiated cells. These, so called, untargeted effects are demonstrated in cells that are the descendants of irradiated cells either directly or via media transfer (radiation-induced genomic instability) or in cells that have communicated with irradiated cells (radiation-induced bystander effects). Radiation-induced genomic instability is characterized by a number of delayed responses including chromosomal abnormalities, gene mutations and cell death. Bystander effects include increases or decreases in damage-inducible and stress-related proteins, increases or decreases in reactive oxygen and nitrogen species, cell death or cell proliferation, cell differentiation, radioadaptation, induction of mutations and chromosome aberrations and chromosomal instability. The phenotypic expression of untargeted effects and the potential consequences of these effects in tissues reflect a balance between the type of bystander signals produced and the responses of cell populations to such signals, both of which may be significantly influenced by cell type and genotype. Thus, in addition to targeted effects of damage induced directly in cells by irradiation, a variety of untargeted effects may also make important short-term and long-term contributions to determining overall outcome after radiation exposures.

Animals↗
PubMed2002

The human papillomavirus type 16 E6 and E7 oncoproteins independently induce numerical and structural chromosome instability.

The development of genomic instability is a hallmark of high-risk human papillomavirus (HPV) associated cervical carcinogenesis. We have previously shown that the HPV-16 E7 oncoprotein rapidly subverts mitotic fidelity by inducing abnormal centrosome numbers and multipolar mitotic spindles. Here we report that expression of HPV-16 E6 and E7 independently results in various mitotic abnormalities. HPV-16 E6 and E7 were each associated with unaligned or lagging chromosomal material, indicating relaxation of spindle checkpoint control. Moreover, by overwhelming checkpoint control mechanisms that may prevent cells with multiple spindle poles to enter anaphase, expression of HPV-16 E6 and E7 leads to a small but significant number of cells with altered polarity at later stages of the cell division process. In addition to changes that have the potential to give rise to numerical chromosome imbalances, we discovered that expression of HPV-16 E7 could trigger anaphase bridge formation to an extent similar to that of high-risk HPV E6. Anaphase bridges typically develop after chromosomal breaks and alterations of chromosomal structure. Further investigation of mechanisms by which HPV-16 E6 and E7 contribute to the destabilization of the host cell genome revealed that both high-risk HPV oncoproteins induce DNA damage. Moreover, expression of HPV-16 E7 was associated with an increased number of cells exhibiting nuclear foci of phosphorylated histone H2AX as well as activation of cell cycle checkpoints triggered by DNA repair. Our results therefore suggest that HPV oncoproteins are a source for both numerical and structural chromosome instability during HPV-associated carcinogenesis.

Anaphase↗
PubMed2005

Direct single gene mutational events account for radiation-induced intestinal adenoma yields in Apc(Min/+) mice.

Data on the induction of small intestinal tumors, predominantly adenomas, by X radiation in Apc(Min/+) mice are reported. Comparison of these incidences with estimates of radiation-induced direct single gene mutation frequencies taken from the literature support the hypothesis that direct mutational loss of Apc+ is the sole requirement for initiation of adenoma. Furthermore, estimates of radiation-induced initiation of adenoma per target stem cell in this animal model are similar to or less than radiation-induced direct somatic gene mutation frequencies. Therefore, while the data reported here do not preclude a role for genomic instability in tumor progression, it is not necessary in this model to postulate the involvement of radiation-induced transmissible genomic instability in initiation of intestinal adenoma.

Adenoma↗
PubMed2025

Modern biology of extrachromosomal DNA: A decade-long voyage of discovery.

Genomic instability is a hallmark of cancer and is a major driving force of tumorigenesis. A key manifestation of genomic instability is the formation of extrachromosomal DNAs (ecDNAs) - acentric, circular DNA molecules ranging from 50 kb to 5 Mb in size, distinct from chromosomes. Ontological studies have revealed that ecDNA serves as a carrier of oncogenes, immunoregulatory genes, and enhancers, capable of driving elevated transcription of its cargo genes and cancer heterogeneity, leading to rapid tumor evolution and therapy resistance. Although ecDNA was documented over half a century ago, the past decade has witnessed a surge in breakthrough discoveries about its biological functions. Here, we systematically review the modern biology of ecDNA uncovered over the last ten years, focusing on how discoveries during this pioneering stage have illuminated our understanding of ecDNA-driven transcription, heterogeneity, and cancer progression. Furthermore, we discuss ongoing efforts to target ecDNA as a novel approach to cancer therapy. This burgeoning field is entering a new phase, poised to reshape our knowledge of cancer biology and therapeutic strategies.

Humans↗
PubMed2005

Variation in apoptosis profiles in radiation-induced genomically unstable cell lines.

Delayed reproductive cell death or lethal mutations in the survivors of irradiated cells is a well-characterized end point associated with radiation-induced genomic instability. Although the mechanism for this delayed lethality has not been identified, it is thought to be a means of eliminating cells that have sustained extensive damage, thus preventing tissue disruption after radiation exposure. In this study we have tested the hypothesis that delayed reproductive cell death in chromosomally unstable GM10115 clones is due to persistently increased levels of apoptosis. Evidence for differences in apoptosis in two representative genomically unstable clones after irradiation is presented. In addition, one of the unstable clones was found to have abnormal levels of apoptosis after radiation exposure. An understanding of apoptosis in genomically unstable clones may provide insight into the maintenance of genomic instability and the mechanism by which genomically unstable cells evade cell death, potentially contributing to carcinogenesis.

Animals↗
PubMed2001

PTEN gene mutations in colorectal cancers displaying microsatellite instability.

To determine the relationship between the mutation of the PTEN gene and genomic instability in human colorectal cancer, we screened the PTEN gene in 32 colorectal cancers (eight cell lines and 24 tissues) displaying microsatellite instability (MSI) and 32 colorectal cancers (six cell lines and 26 tissues) displaying microsatellite stability (MSS). Of 64 samples, six frameshift mutations were identified in six MSI colorectal cancers (two cell lines and four tumor tissues) but not in MSS colorectal cancers. Of the six MSI colorectal cancers containing PTEN mutation, two case (one cell line and one tumor tissue) showed biallelic mutation of PTEN. Furthermore, to compare the frequency of PTEN mutation with that of other MSI target genes, the mononucleotide repeat sequences of TGF-betaRII, BAX, IGFIIR, hMSH6 and hMSH3 were analyzed. The frequencies of frameshift mutation were revealed 78% in TGF-betaRII, 56% in BAX, 46.9% in hMSH3, 37.5% in hMSH6, 21.9% in IGFIIR, and 18.8% in PTEN. These results suggest that the PTEN gene is a target of genomic instability in MSI colorectal tumorigenesis.

Colorectal Neoplasms↗
PubMedDate not supplied

[The reaction of cell population to low level of irradiation].

The results of long-term investigations of the effectivity of low level irradiation (below 0.5 Gy) carried out on the cells in culture and blood human lymphocytes (adults and children) have been brought. In the experiments conducted in the laboratory conditions and in the contaminated with radionuclides regions (after Chernobyl accident) the genomic instability have been discovered. The cell manifestations of the genomic instability have been registered in the progeny of irradiated cells as the decreasing of proliferative activity, the increasing of the frequency of cells with micronuclei, the increasing of cells with sister chromatid exchanges, the late cell death, the absence of the adaptive response ability, the enhancement of the radiosensitivity. The results of the investigations of the adaptive response of blood lymphocytes have been presented. It was shown that in all populations investigated there are individuals without the adaptive response and the individuals with the enhancement of radiosensitivity after adaptive irradiation (0.05 Gy). On the basis of own results and the data of literature the possible mechanisms of low level irradiation effects are discussed. The conclusion is that: a. The population with new properties can be formed after low level irradiation; b. The effects and mechanisms of this effect realization can be different from that after irradiation with high doses.

Adaptation, Physiological↗
PubMed2004

Aging and genetic instability in yeast.

There is a striking link between increasing age and the incidence of cancer in humans. One of the hallmarks of cancer, genomic instability, has been observed in all types of organisms. In the yeast Saccharomyces cerevisiae, it was recently discovered that during the replicative lifespan, aging cells switch to a state of high genomic instability that persists until they die. In considering these and other recent results, we suggest that accumulation of oxidatively damaged protein in aging cells results in the loss of function of gene products critical for maintaining genome integrity. Determining the identity of these proteins and how they become damaged represents a new challenge for understanding the relationship between age and genetic instability.

Gene Expression Regulation, Fungal↗
PubMed2004

Radiation-induced chromosomal instability and gene expression profiling: searching for clues to initiation and perpetuation.

Radiation-induced genomic instability (RIGI) manifests in the progeny of cells surviving ionizing radiation (IR), and can be measured using such endpoints as delayed mutation, micronuclei formation, and chromosomal instability. The frequency of RIGI is relatively high, exceeding the gene mutation rate of IR by orders of magnitude, leading to conjecture that a gene mutation is not the cause of the phenotype. We have started to explore whether differential gene expression patterns are associated with the instability phenotype, in order to shed light on its initiation and perpetuation. Using GM10115 human-hamster hybrid-derived chromosomally stable and radiation-induced unstable clones, gene expression patterns were analyzed using microarray analysis. Two methods were used to find differentially expressed genes, and all candidate genes identified by these methods were under-expressed relative to the chromosomally stable reference sample. Among this set differentially expressed genes identified were two candidates with a relationship to the ubiquitin/proteasome pathway. While follow-up gene expression analyses have confirmed the under-expression of these two genes in some of our chromosomally unstable clones, preliminary functional studies have been unable to demonstrate a link to instability. It is anticipated that as we apply this technology to the study of radiation-induced genomic instability, clues to its onset will be revealed, ultimately contributing to a greater understanding of the mechanisms of radiation carcinogenesis.

Animals↗
PubMed2004

Distinct mechanisms lead to HPRT gene mutations in leukemic cells.

Leukemias are considered malignant clonal disorders arising from the accumulation of mutations in hematopoietic cells; the majority of these mutations are thought to be acquired somatically. Measurement of mutation frequency (Mf) at the hypoxanthine phosphoribosyltransferase (HPRT) locus has been developed as a method for estimating genomic instability. We investigated the Mf in 16 leukemic cell lines to determine whether these cell lines showed evidence of genomic instability. Although some leukemic cell lines had markedly elevated Mfs, the Mfs at the HPRT locus in leukemic cell lines were not always higher than those of B-lymphoblastoid cell lines and T lymphocytes from normal individuals. We were able to identify the HPRT mutation for 159 of 160 individual HPRT mutants. The HPRT mutations were characterized at a molecular level and classified as either gross chromosomal rearrangements (GCRs) or point mutations, such as single-nucleotide substitutions, insertions, or deletions. With rare exceptions, individual leukemic cell lines showed either point mutations or GCR, but not both. Of note, all the cell lines that primarily showed point mutations are known to be defective in mismatch repair machinery.

Adolescent↗
PubMed1999

Rapid structural and epigenetic changes in polyploid and aneuploid genomes.

Recent work with plants has demonstrated that genome instability can be triggered by a change in chromosome number arising from either whole genome duplications (polyploidy) or loss/gain of individual chromosomes (aneuploidy). This genome instability is manifested as rapid structural and epigenetic alterations that can occur somatically or meiotically within a few generations after heteroploid formation. The intrinsic instability of newly formed polyploid and aneuploid genomes has relevance for genome evolution and human carcinogenesis, and points toward recombinational and epigenetic mechanisms that sense and respond to chromosome numerical changes.

Aneuploidy↗
PubMed2005

Clonally expanded T-cell populations in atomic bomb survivors do not show excess levels of chromosome instability.

Radiation-induced genomic instability has been studied primarily in cultured cells, while in vivo studies have been limited. One major obstacle for in vivo studies is the lack of reliable biomarkers that are capable of distinguishing genetic alterations induced by delayed radiation effects from those that are induced immediately after a radiation exposure. Here we describe a method to estimate cytogenetic instability in vivo using chromosomally marked clonal T-cell populations in atomic bomb survivors. The basic idea is that clonal translocations are derived from single progenitor cells that acquired an aberration, most likely after a radiation exposure, and then multiplied extensively in vivo, resulting in a large number of progeny cells that eventually comprise several percent of the total lymphocyte population. Therefore, if chromosome instability began to operate soon after a radiation exposure, an elevated frequency of additional but solitary chromosome aberrations in clonal cell populations would be expected. In the present study, six additional translocations were found among 936 clonal cells examined with the G-band method (0.6%); the corresponding value with multicolor FISH analysis was 1.2% (4/333). Since these frequencies were no higher than 1.2% (219/17,878 cells), the mean translocation frequency observed in control subjects using the G-band method, it is concluded that chromosome instabilities that could give rise to an increased frequency of persisting, exchange-type aberrations were not commonly generated by radiation exposure.

Breast Neoplasms↗
PubMed2025

p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.

Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.

Animals↗
PubMed2004

Chromosome instability in T-cells cultured in the presence of pancuronium or fentanyl.

BACKGROUND: Genomic instability is recognized as a cause of cellular apoptosis and certain drugs that exhibit a proapoptotic effect are also able to induce chromosome damage. Since we found in recent experiments that drugs such as pancuronium and fentanyl exerted an apoptogenic effect on T cells, we studied the capacity of those agents to promote chromosome instability, i.e. chromosome aberrations (CA) and telomeric associations (tas) in peripheral blood lymphocytes. METHODS: Lymphocytes from healthy donors were cultured with pancuronium or fentanyl, using two different concentrations for each drug: 20 and 200 ng/ml for pancuronium and 10 and 30 ng/ml for fentanyl, respectively. Cells were exposed to each concentration of these drugs either for 24 or 48 h. The higher concentration chosen was the same at which we detected the proapoptotic effect in our previous works. Cytogenetic analysis was performed by means of a standard technique and chromosome aberrations or telomeric associations were blindly evaluated by two independent observers. RESULTS: The chromosome aberrations we observed in treated cells were not significantly different from control lymphocytes. However, an unusual rate of telomeric associations (P < 0.001) was detected in cells exposed to both pancuronium and fentanyl, at each concentration tested and at each exposure time of the study. CONCLUSIONS: Fentanyl and pancuronium do not have a direct clastogenic effect on T cultures, but at the same concentrations at which we demonstrated their apoptogenic power, these drugs are able to increase genomic instability through inducing an elevated rate of telomeric associations. Such a capacity could exploit in peripheral T cells the same mitochondrion-mediated signal pathway of apoptosis death.

Adult↗