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PubMed2005

[Complex role of the FA proteins in providing genome stability].

FA is a rare genetic disorder characterized by developmental abnormalities, bone marrow failure and cancer susceptibility. Cells that are derived from patients with FA display spontaneous chromosomal instability and hypersensitivity to DNA crosslinking agents that is used in FA clinical diagnostics. FA is genetically heterogeneous and caused by mutations in at least 11 distinct genes, FANCA, FANCA, B, C, D1, D2, E, F, G, I, J and L. FA proteins interact with various proteins involved in DNA damage response and cell cycle checkpoint regulation, such as: RAD51, BRCA1, BRCA2, ATM or NBS1. Moreover, BRCA2 that plays a crucial role in homologous recombination is one of FA proteins. Collectively, all these data indicate, that the FA pathway is involved in different molecular processes that prevent DNA and control genomic stability, although its precise role still remains undefined.

Apoptosis↗
PubMed2006

Drosophila damaged DNA binding protein 1 contributes to genome stability in somatic cells.

The damaged DNA-binding protein (DDB) complex consists of a heterodimer of p127 (DDB1) and p48 (DDB2) subunits and is believed to have a role in nucleotide excision repair (NER). We used the GAL4-UAS targeted expression system to knock down DDB1 in wing imaginal discs of Drosophila. The knock-down was achieved in transgenic flies using over-expression of inverted repeat RNA of the D-DDB1 gene [UAS-D-DDB1(650)-dsRNA]. As a consequence of RNA interference (RNAi), the fly had a shrunken wing phenotype. The wing spot test showed induced genome instability in transgenic flies with RNAi knock-down of D-DDB1 in wing imaginal discs. When Drosophila larvae with RNAi knock-down of D-DDB1 in wing imaginal discs were treated with the chemical mutagen methyl methanesulfonate (MMS), the frequency of flies with a severely shrunken wing phenotype increased compared to non-treated transgenic flies. These results suggested that DDB1 plays a role in the response to DNA damaged with MMS and in genome stability in Drosophila somatic cells.

Animals↗
PubMed2004

DSS1 is required for RAD51 focus formation and genomic stability in mammalian cells.

BRCA2 is a breast cancer susceptibility gene implicated in the repair of double-strand breaks by homologous recombination with RAD51. BRCA2 associates with a 70-amino-acid protein, DSS1, but the functional significance of this interaction has remained unclear. Recently, deficiency of a DSS1 orthologue in the fungus Ustilago maydis has been shown to cause a defect in recombinational DNA repair. Here we have investigated the consequences of DSS1 depletion in mammalian cells. We show that like BRCA2, DSS1 is required for DNA damage-induced RAD51 focus formation and for the maintenance of genomic stability, indicating a function conserved from lower eukaryotes to humans. However, DSS1 seems to be not required for BRCA2 or RAD51 stability or for BRCA2 and RAD51 to interact, raising the possibility that DSS1 may be required for the BRCA2-RAD51 complex to become associated with sites of DNA damage.

Animals↗
PubMed2001

Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability.

Histone H3 lysine 9 methylation has been proposed to provide a major "switch" for the functional organization of chromosomal subdomains. Here, we show that the murine Suv39h histone methyltransferases (HMTases) govern H3-K9 methylation at pericentric heterochromatin and induce a specialized histone methylation pattern that differs from the broad H3-K9 methylation present at other chromosomal regions. Suv39h-deficient mice display severely impaired viability and chromosomal instabilities that are associated with an increased tumor risk and perturbed chromosome interactions during male meiosis. These in vivo data assign a crucial role for pericentric H3-K9 methylation in protecting genome stability, and define the Suv39h HMTases as important epigenetic regulators for mammalian development.

Aneuploidy↗
PubMed2026

Dynamic chromatin tethering of MDC1 regulates genome stability.

DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions because they disrupt the connectivity of the DNA strand. Homologous recombination (HR) is a high-fidelity DSB repair pathway that copies the sequence spanning the break from a homologous template, but how DNA ends are held together during HR remains unclear. Here we demonstrate that the proline-serine-threonine (PST) repeat region of Mediator of DNA Damage Checkpoint 1 (MDC1) is a multivalent nucleosome-binding domain, sufficient to tether chromatin in multiple contexts. In interphase, the constitutive chromatin association of MDC1 is critical for RAD51 loading and efficient HR. In mitosis, PST-mediated chromatin binding is attenuated by phosphorylation, preventing aberrant chromosomal interactions while preserving DNA tethering by the MDC1-TOPBP1-CIP2A complex. In total, this work demonstrates that the PST repeat region of MDC1 is a multivalent nucleosome-binding domain with tunable affinity that supports DSB repair by HR and maintains genome stability during mitosis.

Genomic Instability↗
PubMed2006

AIMP3 haploinsufficiency disrupts oncogene-induced p53 activation and genomic stability.

AIMP3 (previously known as p18) was shown to up-regulate p53 in response to DNA damage. Here, we show that AIMP3 couples oncogenic stresses to p53 activation to prevent cell transformation. Growth factor- or Ras-dependent induction of p53 was blocked by single allelic loss of AIMP3 as well as by suppression of AIMP3. AIMP3 heterozygous cells became susceptible to cell transformation induced by oncogenes such as Ras or Myc alone. The transformed AIMP3+/- cells showed severe abnormality in cell division and chromosomal structure. Thus, AIMP3 plays crucial roles in p53-mediated tumor-suppressive response against oncogenic stresses via differential activation of ATM and ATR, and in the maintenance of genomic stability.

Alleles↗
PubMed2004

Influence of tissue origins and external microenvironment on porcine foetal fibroblast growth, proliferative life span and genome stability.

One of the challenges of manipulating genes in primary cells is that the cells have a finite proliferation capacity. This, combined with the lower gene targeting efficiency of somatic cells, makes identification of targeted clones very difficult. The objective of this study was to establish a system that allows porcine foetal fibroblasts to reach their maximal proliferation capacity in vitro. The influence of fibroblast origin, stage of foetal development, cell seeding densities and concentration of foetal bovine serum (FBS) on the population doublings, the percentage of beta-galactosidase-activity-positive cells and the genome stability of foetal fibroblasts during in vitro culture was investigated. It was found that porcine foetal fibroblasts could be cultured for over 80 population doublings in the appropriate culture system. Fibroblasts from earlier stages of foetal development were better candidate cells than those from the later stages. Cells from the heart were more actively proliferative and more resistant to replicative senescence than those from the liver. Compared to 10% FBS content, 15% FBS provided better homeostatic support, not only to proliferative performance, but also in maintaining a normal karyotype. In addition, the proliferative life span of porcine foetal fibroblasts is also dependent on seeding density of the culture.

Animals↗
PubMed2006

Contribution of Trf4/5 and the nuclear exosome to genome stability through regulation of histone mRNA levels in Saccharomyces cerevisiae.

Balanced levels of histones are crucial for chromosome stability, and one major component of this control regulates histone mRNA amounts. The Saccharomyces cerevisiae poly(A) polymerases Trf4 and Trf5 are involved in a quality control mechanism that mediates polyadenylation and consequent degradation of various RNA species by the nuclear exosome. None of the known RNA targets, however, explains the fact that trf mutants have specific cell cycle defects consistent with a role in maintaining genome stability. Here, we investigate the role of Trf4/5 in regulation of histone mRNA levels. We show that loss of Trf4 and Trf5, or of Rrp6, a component of the nuclear exosome, results in elevated levels of transcripts encoding DNA replication-dependent histones. Suggesting that increased histone levels account for the phenotypes of trf mutants, we find that TRF4 shows synthetic genetic interactions with genes that negatively regulate histone levels, including RAD53. Moreover, synthetic lethality of trf4Delta rad53Delta is rescued by reducing histone levels whereas overproduction of histones is deleterious to trf's and rrp6Delta mutants. These results identify TRF4, TRF5, and RRP6 as new players in the regulation of histone mRNA levels in yeast. To our knowledge, the histone transcripts are the first mRNAs that are upregulated in Trf mutants.

Blotting, Northern↗
PubMed2005

Poly(ADP-ribosylation) and genomic stability.

Poly(ADP-ribose) polymerases (PARPs) catalyze the synthesis of ADP-ribose polymers and attach them to specific target proteins. To date, 6 members of this protein family in humans have been characterized. The best-known PARP, PARP-1, is located within the nucleus and has a major function in DNA repair but also in the execution of cell death pathways. Other PARP enzymes appear to carry out highly specific functions. Most prominently, the tankyrases modify telomere-binding proteins and thereby regulate telomere maintenance. Since only a single enzyme, poly(ADP-ribose) glycohydrolase (PARG), has been identified, which degrades poly(ADP-ribose), it is expected that this protein has important roles in PARP-mediated regulatory processes. This review summarizes recent observations indicating that poly(ADP-ribosylation) represents a major mechanism to regulate genomic stability both when DNA is damaged by exogenous agents and during cell division.

Adenosine Diphosphate Ribose↗
PubMed2000

Elevated UV-B radiation reduces genome stability in plants.

Long-term depletion of the stratospheric ozone layer contributes to an increase in terrestrial solar ultraviolet-B radiation. This has deleterious effects on living organisms, such as DNA damage. When exposed to elevated ultraviolet-B radiation (UV-B; 280-315 nm), plants display a wide variety of physiological and morphological responses characterized as acclimation and adaptation. Here we show, using special sun simulators, that elevated solar UV-B doses increase the frequency of somatic homologous DNA rearrangements in Arabidopsis and tobacco plants. Increases in recombination are accompanied by a strong induction of photolyase and Rad51 gene expression. These genes are putatively involved in major DNA repair pathways, photoreactivation and recombination repair. In mutant Arabidopsis plants that are deficient in photoreactivating ultraviolet-induced cyclobutane pyrimidine dimers, recombination under elevated UV-B regimes greatly exceeds wild-type levels. Our results show that homologous recombination repair pathways might be involved in eliminating UV-B-induced DNA lesions in plants. Thus, increases in terrestrial solar UV-B radiation as forecasted for the early 21st century may affect genome stability in plants.

Arabidopsis↗
PubMed2004

ELG1, a regulator of genome stability, has a role in telomere length regulation and in silencing.

Telomeres, the natural ends of eukaryotic chromosomes, prevent the loss of chromosomal sequences and preclude their recognition as broken DNA. Telomere length is kept under strict boundaries by the action of various proteins, some with negative and others with positive effects on telomere length. Recently, data have been accumulating to support a role for DNA replication in the control of telomere length, although through a currently poorly understood mechanism. Elg1p, a replication factor C (RFC)-like protein of yeast, contributes to genome stability through a putative replication-associated function. Here, we show that Elg1p participates in negative control of telomere length and in telomeric silencing through a replication-mediated pathway. We show that the telomeric function of Elg1 is independent of recombination and completely dependent on an active telomerase. Additionally, this function depends on yKu and DNA polymerase. We discuss alternative models to explain how Elg1p affects telomere length.

Base Sequence↗
PubMed2001

Securing genome stability by orchestrating DNA repair: removal of radiation-induced clustered lesions in DNA.

In addition to double- and single-strand DNA breaks and isolated base modifications, ionizing radiation induces clustered DNA damage, which contains two or more lesions closely spaced within about two helical turns on opposite DNA strands. Post-irradiation repair of single-base lesions is routinely performed by base excision repair and a DNA strand break is involved as an intermediate. Simultaneous processing of lesions on opposite DNA strands may generate double-strand DNA breaks and enhance nonhomologous end joining, which frequently results in the formation of deletions. Recent studies support the possibility that the mechanism of base excision repair contributes to genome stability by diminishing the formation of double-strand DNA breaks during processing of clustered lesions.

Animals↗
PubMed2003

Longevity regulation in Saccharomyces cerevisiae: linking metabolism, genome stability, and heterochromatin.

When it was first proposed that the budding yeast Saccharomyces cerevisiae might serve as a model for human aging in 1959, the suggestion was met with considerable skepticism. Although yeast had proved a valuable model for understanding basic cellular processes in humans, it was difficult to accept that such a simple unicellular organism could provide information about human aging, one of the most complex of biological phenomena. While it is true that causes of aging are likely to be multifarious, there is a growing realization that all eukaryotes possess surprisingly conserved longevity pathways that govern the pace of aging. This realization has come, in part, from studies of S. cerevisiae, which has emerged as a highly informative and respected model for the study of life span regulation. Genomic instability has been identified as a major cause of aging, and over a dozen longevity genes have now been identified that suppress it. Here we present the key discoveries in the yeast-aging field, regarding both the replicative and chronological measures of life span in this organism. We discuss the implications of these findings not only for mammalian longevity but also for other key aspects of cell biology, including cell survival, the relationship between chromatin structure and genome stability, and the effect of internal and external environments on cellular defense pathways. We focus on the regulation of replicative life span, since recent findings have shed considerable light on the mechanisms controlling this process. We also present the specific methods used to study aging and longevity regulation in S. cerevisiae.

Gene Expression Regulation, Fungal↗
PubMed2005

Ddb1 controls genome stability and meiosis in fission yeast.

The human UV-damaged DNA-binding protein Ddb1 associates with cullin 4 ubiquitin ligases implicated in nucleotide excision repair (NER). These complexes also contain the signalosome (CSN), but NER-relevant ubiquitination targets have not yet been identified. We report that fission yeast Ddb1, Cullin 4 (Pcu4), and CSN subunits Csn1 and Csn2 are required for degradation of the ribonucleotide reductase (RNR) inhibitor protein Spd1. Ddb1-deficient cells have >20-fold increased spontaneous mutation rate. This is partly dependent on the error-prone translesion DNA polymerases. Spd1 deletion substantially reduced the mutation rate, suggesting that insufficient RNR activity accounts for approximately 50% of observed mutations. Epistasis analysis indicated that Ddb1 contributed to mutation avoidance and tolerance to DNA damage in a pathway distinct from NER. Finally, we show that Ddb1/Csn1/Cullin 4-mediated Spd1 degradation becomes essential when cells differentiate into meiosis. These results suggest that Ddb1, along with Cullin 4 and the signalosome, constitute a major pathway controlling genome stability, repair, and differentiation via RNR regulation.

Cell Cycle Proteins↗
PubMed2004

The histone acetyltransferase GCN5 modulates the retrograde response and genome stability determining yeast longevity.

Transcriptional silencing decreases at both subtelomeric and silent mating-type loci and increases at the ribosomal DNA locus during the replicative life span of the yeast Saccharomyces cerevisiae . Evidence exists that epigenetic changes in the regulatory state of chromatin may be a causal factor in determining yeast longevity and that histone deacetylases play a role. The significance of histone acetylation has been examined here in more detail. Deletion of the histone acetyltransferase gene GCN5 suppressed the extension of replicative life span afforded by the induction of the retrograde response, which signals mitochondrial dysfunction and leads to changes in nuclear gene expression. It was difficult to ascribe this effect to changes in transcriptional silencing in any of the three known types of heterochromatin. However, a promoter related effect was uncovered by the participation of GCN5 in the induction of the retrograde response. Gcn5p and the retrograde signal transducer Rtg2p are components of the histone acetyltransferase coactivator complex SLIK. Rtg2p blocks the production of extrachromosomal ribosomal DNA circles when it is not engaged in transmission of the retrograde signal. Deletion of GCN5 , which disrupts the integrity of SLIK, suppressed circle accumulation. The results indicate that Gcn5p and SLIK impact the interplay between the retrograde response signal and Rtg2p with consequences for the induction of the response and circle production. Rtg2p and Gcn5p in the SLIK complex link metabolism to stress responses, chromatin-dependent gene regulation, and genome stability in yeast aging.

Base Sequence↗
PubMed2006

Telomere dynamics in genome stability.

The past several years have seen an increasing interest in telomere recombinational interactions that provide many functions in telomere capping, in telomere size homeostasis and in overcoming the catastrophic effects of telomerase deficiency. Several key recombination mechanisms have emerged from recent investigations. In the yeasts, these mechanisms include exchange between subtelomeric regions and telomere sequences, rapid telomere expansion and telomere deletion. These processes proceed by pathways that use both the cellular recombination machinery and novel mechanisms such as rolling circle replication. The insights gained from recent studies extend our understanding of similar processes in higher eukaryotes and suggest that the recombinational dynamics of telomeres have additional roles that contribute to genomic stability and instability.

Animals↗
PubMed2003

Drosophila p53 preserves genomic stability by regulating cell death.

When animal cells are exposed to stressful conditions, the tumor suppressor protein p53 restrains growth by promoting an arrested cell cycle or initiating a cell death program. How these distinct fates are specified through the action of a single protein is not known. To study its functions in vivo we produced a targeted mutation at the Drosophila p53 (Dmp53) locus. We show that Dmp53 is required for damage-induced apoptosis but not for cell-cycle arrest. Dmp53 function is also required for damage-induced transcription of two tightly linked cell death activators, reaper and sickle. When challenged by ionizing radiation, Dmp53 mutants exhibit radiosensitivity and genomic instability. Hence, elevated mutant loads were not caused by defective checkpoint functions but instead correlated with failures in p53-associated cell death. Our studies support the notion that core ancestral functions of the p53 gene family are intimately coupled to cell death as an adaptive response to maintain genomic stability.

Animals↗
PubMed1996

SGS1, a homologue of the Bloom's and Werner's syndrome genes, is required for maintenance of genome stability in Saccharomyces cerevisiae.

The Saccharomyces cerevisiae SGS1 gene is homologous to Escherichia coli RecQ and the human BLM and WRN proteins that are defective in the cancer-prone disorder Bloom's syndrome and the premature aging disorder Werner's syndrome, respectively. While recQ mutants are deficient in conjugational recombination and DNA repair, Bloom's syndrome cell lines show hyperrecombination. Bloom's and Werner's syndrome cell lines both exhibit chromosomal instability, sgs1 delta strains show mitotic hyperrecombination, as do Bloom's cells. This was manifested as an increase in the frequency of interchromosomal homologous recombination, intrachromosomal excision recombination, and ectopic recombination. Hyperrecombination was partially independent of both RAD52 and RAD1. Meiotic recombination was not increased in sgs1 delta mutants, although meiosis I chromosome missegregation has been shown to be elevated sgs1 delta suppresses the slow growth of a top3 delta strain lacking topoisomerase III. Although there was an increase in subtelomeric Y' instability in sgs1 delta strains due to hyperrecombination, no evidence was found for an increase in the instability of terminal telomeric sequences in a top3 delta or a sgs1 delta strain. This contrasts with the telomere maintenance defects of Werner's patients. We conclude that the SGS1 gene product is involved in the maintenance of genome stability in S. cerevisiae.

Adenosine Triphosphatases↗