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Results for “Genome Stability”

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PubMed2003

Applications of RNA interference for studies in DNA damage processing, genome stability, mutagenesis, and cancer.

RNA interference, discovered only five years ago, is an important system for the control of gene expression. It is also quickly becoming a valuable experimental tool as it allows investigators to knock down the level of expression of specific genes. In this paper, we review some applications of this technology for studies in DNA damage processing, genome stability, mutagenesis, and cancer.

Animals↗
PubMed2006

Genomic stability and physiological assessments of live offspring sired by a bull clone, Starbuck II.

It appears that overt phenotypic abnormalities observed in some domestic animal clones are not transmitted to their progeny. The current study monitored Holstein heifers sired by a bull clone, Starbuck II, from weaning to puberty. Genomic stability was assessed by telomere length status and chromosomal analysis. Growth parameters, blood profiles, physical exams and reproductive parameters were assessed for 12 months (and compared to age-matched control heifers). Progeny sired by the clone bull did not differ (P>0.05) in weight, length and height compared to controls. However, progeny had lower heart rates (HR) (P=0.009), respiratory rates (RR) (P=0.007) and body temperature (P=0.03). Hematological profiles were within normal ranges and did not differ (P>0.05) between both groups. External and internal genitalia were normal and both groups reached puberty at expected ages. Progeny had two or three ovarian follicular waves per estrous cycle and serum progesterone concentrations were similar (P=0.99) to controls. Telomere lengths of sperm and blood cells from Starbuck II were not different (P>0.05) than those of non-cloned cattle; telomere lengths of progeny were not different (P>0.05) from age-matched controls. In addition, progeny had normal karyotypes in peripheral blood leukocytes compared to controls (89.1% versus 86.3% diploid, respectively). In summary, heifers sired by a bull clone had normal chromosomal stability, growth, physical, hematological and reproductive parameters, compared to normal heifers. Furthermore, they had moderate stress responses to routine handling and restraint.

Aging↗
PubMed2003

The genome stability in Corynebacterium species due to lack of the recombinational repair system.

Corynebacterium species are members of gram-positive bacteria closely related to Mycobacterium species, both of which are classified into the same taxonomic order Actinomycetales. Recently, three corynebacteria, Corynebacterium efficiens, Corynebacterium glutamicum, and Corynebacterium diphtheriae have been sequenced independently. We found that the order of orthologous genes in these species has been highly conserved though it has been disrupted in Mycobacterium species. This synteny suggests that corynebacteria have rarely undergone extensive genome rearrangements and have maintained ancestral genome structures even after the divergence of corynebacteria and mycobacteria. This is the first report that the genome structures have been conserved in free-living bacteria such as C. efficiens and C. glutamicum, although it has been reported that obligate parasites such as Mycoplasma and Chlamydia have the stable genomes. The comparison of recombinational repair systems among the three corynebacteria and Mycobacterium tuberculosis suggested that the absence of recBCD genes in corynebacteria be responsible for the suppression of genome shuffling in the species. The genome stability in Corynebacterium species will give us hints of the speciation mechanism with the non-shuffled genome, particularly the importance of horizontal gene transfer and nucleotide substitution in the genome.

Corynebacterium↗
PubMed2002

Mammalian Rad51C contributes to DNA cross-link resistance, sister chromatid cohesion and genomic stability.

The eukaryotic Rad51 protein is a structural and functional homolog of Escherichia coli RecA with a role in DNA repair and genetic recombination. Five paralogs of Rad51 have been identified in vertebrates, Rad51B, Rad51C, Rad51D, Xrcc2 and Xrcc3, which are also implicated in recombination and genome stability. Here, we identify a mammalian cell mutant in Rad51C. We show that the Chinese hamster cell mutant, CL-V4B, has a defect in Rad51C. Sequencing of the hamster Rad51C cDNA revealed a 132 bp deletion corresponding to an alternatively spliced transcript with lack of exon 5. CL-V4B was hypersensitive to the interstrand cross-linking agents mitomycin C (MMC) and cisplatinum, the alkylating agent methyl methanesulfonate and the topoisomerase I inhibitor campthotecin and showed impaired Rad51 foci formation in response to DNA damage. The defect in Rad51C also resulted in an increase of spontaneous and MMC-induced chromosomal aberrations as well as a lack of induction of sister chromatid exchanges. However, centrosome formation was not affected. Intriguingly, a reduced level of sister chromatid cohesion was found in CL-V4B cells. These results reveal a role for Rad51C that is unique among the Rad51 paralogs.

Amino Acid Sequence↗
PubMed1999

A role for PML and the nuclear body in genomic stability.

The PML gene of acute promyelocytic leukemia (APL) encodes a cell-growth and tumor suppressor. PML localizes to discrete nuclear bodies (NBs) that are disrupted in APL cells. The Bloom syndrome gene BLM encodes a RecQ DNA helicase, whose absence from the cell results in genomic instability epitomized by high levels of sister-chromatid exchange (SCE) and cancer predisposition. We show here that BLM co-localizes with PML to the NB. In cells from persons with Bloom syndrome the localization of PML is unperturbed, whereas in APL cells carrying the PML-RARalpha oncoprotein, both PML and BLM are delocalized from the NB into microspeckled nuclear regions. Treatment with retinoic acid (RA) induces the relocalization of both proteins to the NB. In primary PML-/- cells, BLM fails to accumulate in the NB. Strikingly, in PML-/- cells the frequency of SCEs is increased relative to PML+/+ cells. These data demonstrate that BLM is a constituent of the NB and that PML is required for its accumulation in these nuclear domains and for the normal function of BLM. Thus, our findings suggest a role for BLM in APL pathogenesis and implicate the PML NB in the maintenance of genomic stability.

Adenosine Triphosphatases↗
PubMed2005

DNA repair, genome stability, and aging.

Aging can be defined as progressive functional decline and increasing mortality over time. Here, we review evidence linking aging to nuclear DNA lesions: DNA damage accumulates with age, and DNA repair defects can cause phenotypes resembling premature aging. We discuss how cellular DNA damage responses may contribute to manifestations of aging. We review Sir2, a factor linking genomic stability, metabolism, and aging. We conclude with a general discussion of the role of mutant mice in aging research and avenues for future investigation.

Animals↗
PubMed2005

New talents for an old acquaintance: the SR protein splicing factor ASF/SF2 functions in the maintenance of genome stability.

ASF/SF2 is a well-studied SR protein that plays important roles in premRNA splicing and other aspects of RNA metabolism. Genetic inactivation experiments have revealed the fundamental roles of ASF/SF2 and other SR proteins in cell viability and animal development. However, the nature of the events triggered by in vivo depletion of ASF/SF2 remained largely elusive. Recently, we have demonstrated a significant function of ASF/SF2 in the maintenance of genome stability by preventing the formation of R loops, which provided new insights into the essential roles of ASF/SF2 in cellular physiology.

Genomic Instability↗
PubMed2005

Progression elevated gene-3 (PEG-3) induces pleiotropic effects on tumor progression: modulation of genomic stability and invasion.

Progression elevated gene-3 (PEG-3) is a novel rodent gene, identified and cloned by subtraction hybridization, that associates with transformation progression in virus- and oncogene-transformed rat embryo (RE) cells. Previous reports document that ectopic expression of PEG-3 in rodent or human tumor cells produces an aggressive transformed/tumorigenic phenotype. Moreover, PEG-3 expression in rodent tumor cells correlates directly with genomic instability, as indicated by chromosomal alterations and gene amplification, and it promotes angiogenesis. The present studies were designed to further elucidate the functional significance and role of PEG-3 in cancer progression with a specific focus on genomic instability and cancer invasion. Genomic instability was assessed by micronucleus assays and staining of centrosomes to define centrosomal amplification. Immunocytochemical observations revealed that overexpression of PEG-3 in transformed rodent cells induced a loss of chromosomes as established by the appearance of micronuclei and staining of the centrosomes with gamma-tubulin antibody, thereby confirming centrosome amplification. Overexpression of PEG-3 modulated the expression of several genes involved in centrosomal duplication, such as p21CIP1/WAF1/MDA-6, nucleophosmin (NPM), and aurora-A kinase. In vitro invasion of transformed rodent cells was augmented by PEG-3, which correlated with an increase in the transcription and activity of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), which play important roles in local invasion during cancer progression. These findings demonstrate that PEG-3 plays a central role in augmenting tumor progression by modulating several critical parameters of the carcinogenic process, such as genomic stability and local tumor cell invasion.

Animals↗
PubMed2006

Evidence that Spt2/Sin1, an HMG-like factor, plays roles in transcription elongation, chromatin structure, and genome stability in Saccharomyces cerevisiae.

Spt2/Sin1 is a DNA binding protein with HMG-like domains that has been suggested to play a role in chromatin-mediated transcription in Saccharomyces cerevisiae. Previous studies have suggested models in which Spt2 plays an inhibitory role in the initiation of transcription of certain genes. In this work, we have taken several approaches to study Spt2 in greater detail. Our results have identified previously unknown genetic interactions between spt2Delta and mutations in genes encoding transcription elongation factors, including members of the PAF and HIR/HPC complexes. In addition, genome-wide and gene-specific chromatin immunoprecipitation analyses suggest that Spt2 is primarily associated with coding regions in a transcription-dependent fashion. Furthermore, our results show that Spt2, like other elongation factors, is required for the repression of transcription from a cryptic promoter within a coding region and that Spt2 is also required for repression of recombination within transcribed regions. Finally, we provide evidence that Spt2 plays a role in regulating the levels of histone H3 over transcribed regions. Taken together, our results suggest a direct link for Spt2 with transcription elongation, chromatin dynamics, and genome stability.

Chromatin↗
PubMed2006

DNA precursor metabolism and genomic stability.

Intracellular concentrations of the four deoxyribonucleoside triphosphates (dNTPs) are closely regulated, and imbalances in the four dNTP pools have genotoxic consequences. Replication errors leading to mutations can occur, for example, if one dNTP in excess drives formation of a non-Watson-Crick base pair or if it forces replicative DNA chain elongation past a mismatch before DNA polymerase can correct the error by 3' exonuclease proofreading. This review focuses on developments since 1994, when the field was last reviewed comprehensively. Emphasis is placed on the following topics: 1) novel aspects of dNTP pool regulation, 2) dNTP pool asymmetries as mutagenic determinants, 3) dNTP metabolism and hypermutagenesis of retroviral genomes, 4) dNTP metabolism and mutagenesis in the mitochondrial genome, 5) chemical modification of nucleotides as a premutagenic event, 6) relationships between dNTP metabolism, genome stability, aging, and cancer.

Animals↗
PubMed2004

HSP70 and genomic stability.

The 70 kDa heat shock proteins (HSP70s) were initially identified by their elevated expression following hyperthermic cell stress, however, these highly conserved proteins also protect critical cellular functions from a wider range of important environmental and physiological stresses. At least one result of HSP70 expression is inhibition of stress induced caspase activation as well as downstream events in the apoptotic cell death pathway. HSP70 have been reported upregulated in tumor cells, selective inhibition of such proteins might be valuable approach to treat cancer. A recent study revealed that cells with inactivated HSP70 displayed telomere instability and high frequency of spontaneous chromosomal aberrations, indicating a possible role for HSP70 proteins in the maintenance of genomic stability.

Animals↗
PubMed2005

ATM signaling and genomic stability in response to DNA damage.

DNA double strand breaks represent the most threatening lesion to the integrity of the genome in cells exposed to ionizing radiation and radiomimetic chemicals. Those breaks are recognized, signaled to cell cycle checkpoints and repaired by protein complexes. The product of the gene (ATM) mutated in the human genetic disorder ataxia-telangiectasia (A-T) plays a central role in the recognition and signaling of DNA damage. ATM is one of an ever growing number of proteins which when mutated compromise the stability of the genome and predispose to tumour development. Mechanisms for recognising double strand breaks in DNA, maintaining genome stability and minimizing risk of cancer are discussed.

Animals↗
PubMed2002

BRCA2 homolog required for proficiency in DNA repair, recombination, and genome stability in Ustilago maydis.

In a screen for DNA repair-defective mutants in the fungus Ustilago maydis, a gene encoding a BRCA2 family member, designated here as Brh2, was identified. A brh2 null allele was found to be defective in allelic recombination, meiosis, and repair of gaps and ionizing radiation damage to the same extent as rad51. Frequent marker loss in meiosis and diploid formation suggested that genomic instability was associated with brh2. This notion was confirmed by molecular karyotype analysis, which revealed gross chromosomal alterations associated with brh2. Yeast two-hybrid analysis indicated interaction between Brh2 and Rad51. Recapitulation in U. maydis of defects in DNA repair and genome stability associated with brh2 means that the BRCA2 gene family is more widespread than previously thought.

Amino Acid Sequence↗
PubMed1996

Requirement of the yeast MSH3 and MSH6 genes for MSH2-dependent genomic stability.

Defects in DNA mismatch repair result in instability of simple repetitive DNA sequences and elevated levels of spontaneous mutability. The human G/T mismatch binding protein, GTBP/p160, has been suggested to have a role in the repair of base-base and single nucleotide insertion-deletion mismatches. Here we examine the role of the yeast GTBP homolog, MSH6, in mismatch repair. We show that both MSH6 and MSH3 genes are essential for normal genomic stability. Interestingly, although mutations in either MSH3 or MSH6 do not cause the extreme microsatellite instability and spontaneous mutability observed in the msh2 mutant, yeast cells harboring null mutations in both the MSH3 and MSH6 genes exhibit microsatellite instability and mutability similar to that in the msh2 mutant. Results from epistasis analyses indicate that MSH2 functions in mismatch repair in conjunction with MSH3 or MSH6 and that MSH3 and MSH6 constitute alternate pathways of MSH2-dependent mismatch repair.

Amino Acid Sequence↗
PubMed2003

The BRCA2-interacting protein DSS1 is vital for DNA repair, recombination, and genome stability in Ustilago maydis.

DSS1 encodes a small acidic protein shown in recent structural studies to interact with the DNA binding domain of BRCA2. Here we report that an ortholog of DSS1 is present in Ustilago maydis and associates with Brh2, the BRCA2-related protein, thus recapitulating the protein partnership in this genetically amenable fungus. Mutants of U. maydis deleted of DSS1 are extremely radiation sensitive, deficient in recombination, defective in meiosis, and disturbed in genome stability; these phenotypes mirror previous observations of U. maydis mutants deficient in Brh2 or Rad51. These findings conclusively show that Dss1 constitutes a protein with a significant role in the recombinational repair pathway in U. maydis, and imply that it plays a similar key role in the recombination systems of organisms in which recombinational repair is BRCA2 dependent.

BRCA2 Protein↗
PubMed2004

Genome stability of vtc1, tt4, and tt5 Arabidopsis thaliana mutants impaired in protection against oxidative stress.

Reactive oxygen species (ROS) are formed upon normal cellular metabolism or influence of environmental factors and, at normal levels, they play an important physiological role. However, at elevated levels, radicals are toxic and extremely dangerous to all cellular components, including DNA. To efficiently protect themselves, plants have developed sophisticated mechanisms for radical screening and scavenging. In this paper, we analyzed the genome stability of several plant mutants impaired in the protection against free radicals. We crossed the well-known uidA recombination reporter line 651 to flavonoid (tt4 and tt5) and Vitamin C (vtc1)-deficient plants. We found that in all lines tested, both spontaneous and induced (UVC and Rose Bengal (RB)) recombination was higher than in the original 651 parental line. The mRNA expression levels of various DNA repair (RAD1, RAD54-like, MSH3) as well as radical scavenging genes (GPx1, CAT, FSD3) exhibited substantial differences in both control and induced conditions. Our data show that plants impaired in certain aspects of the protection against elevated levels of free radicals induce the production of scavenging enzymes earlier than wild-type (wt) plants, and the higher level of radical species results in the increased incidence of spontaneous double-strand breaks resulting in a higher expression of DNA repair genes.

Arabidopsis↗
PubMed2000

The Tetrahymena p80/p95 complex is required for proper telomere length maintenance and micronuclear genome stability.

The telomerase enzyme adds simple sequence repeats to chromosome ends. Telomerases share two essential subunits, telomerase RNA and telomerase reverse transcriptase, that associate with species-specific proteins of predominantly unknown functions. The Tetrahymena p80/p95 complex can coimmunopurify active telomerase from cell extract, and recombinant p80/p95 can interact directly with telomerase RNA and single-stranded telomeric DNA in vitro. Here, we test the functions of p80/p95 in vivo. Surprisingly, telomerase RNA accumulation and telomerase activity in cell extract are unaffected by loss of the genes encoding p80/p95. However, in the absence of p80/p95, telomeres become elongated in both macronuclei and micronuclei. Micronuclear chromosome maintenance is also compromised. These findings suggest that p80/p95 functions to maintain appropriate telomere length and micronuclear genomic stability but does so in a manner different than previously anticipated.

Animals↗
PubMed2006

The human RNA surveillance factor UPF1 is required for S phase progression and genome stability.

The eukaryotic nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs carrying premature stop codons (PTC). In humans, NMD depends on the RNA- and DNA-dependent 5'-3' helicase UPF1 and six other gene products referred to as SMG1, UPF2, UPF3, EST1A/SMG6, EST1B/SMG5, and EST1C/SMG7. The NMD machinery is also thought to coordinate mRNA nuclear export and translation and to regulate the levels of several physiologic transcripts. Furthermore, in a process named SMD, UPF1 promotes degradation of mRNAs that are bound by Staufen 1. Intriguingly, SMG1 and EST1A/SMG6 function also in DNA repair and telomere maintenance, respectively. Here, we show that UPF1 is also required for genome stability. shRNA-mediated depletion of UPF1 causes human cells to arrest early in S phase, inducing an ATR-dependent DNA-damage response. A fraction of hyperphosphorylated UPF1 associates with chromatin of unperturbed cells, and chromatin association increases in S phase and upon gamma irradiation. ATR phosphorylates UPF1 both in vitro and in vivo, and shRNA-mediated downregulation of ATR diminished the association of UPF1 with chromatin, although it did not affect NMD. Physical interaction of UPF1 with DNA polymerase delta suggests a role for human UPF1 in DNA synthesis during replication or repair.

Ataxia Telangiectasia Mutated Proteins↗