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PubMed1998

1st MRC Human Genetics Symposium: maintenance of genomic stability.

This meeting served to juxtapose the fundamental studies on the distinct pathways which maintain genomic stability with work that addresses the phenotypic consequences of loss of genomic stability in humans. This created an exciting environment where we were prompted to think about the links between fundamental and applied research. It was also a forum where new ideas could be formed that will hopefully fuel interesting research in human disease. As we place the genome projects into perspective, the ideas arising from meetings such as the 1st MRC Human Genetics Symposium might be expected to guide studies that will reveal the molecular defects which underlie some of the more impenetrable phenotypes of human diseases.

Animals↗
PubMed2002

Roles of the Werner syndrome protein in pathways required for maintenance of genome stability.

Werners syndrome is a disease of premature aging where the patients appear much older than their chronological age. The gene codes for a protein that is a helicase and an exonuclease, and recently we have learned about some of its protein interactions. These interactions are being discussed as they shed light on the molecular pathways in which Werner protein participates. Insight into these pathways brings insight into the aging process.

Catalysis↗
PubMed2001

Maintenance of genomic integrity in mammalian kidney cells exposed to hyperosmotic stress.

Changes in environmental salinity/osmolality impose an osmotic stress upon cells because, if left uncompensated, such changes will alter the conserved intracellular ionic milieu and macromolecular density, for which cell metabolism in most extant cells has been optimized. Cell responses to osmotic stress include rapid posttranslational and slower transcriptional events for the compensatory regulation of cell volume, intracellular electrolyte concentrations, and protein stability/activity. Changes in external osmolality are perceived by osmosensors that control the activation of signal transduction pathways giving rise to the above responses. We have recently shown that the targets of such pathways include cell cycle-regulatory and DNA damage-inducible genes (reviewed in Kültz, D., 2000. Environmental stressors and gene responses, Elsevier, Amsterdam. pp 157-179). Moreover, recent evidence suggests that hyperosmotic stress causes chromosomal aberrations and DNA double-strand breaks in mammalian cells. We propose that the modulation of cell cycle checkpoints and the preservation of genomic integrity are important aspects of cellular osmoprotection and as essential for cellular osmotic stress resistance as the capacity for cell volume regulation and maintaining inorganic ion homeostasis and protein stability/activity.

Animals↗
PubMed1999

Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53.

In this review we describe the multiple functions of p53 in response to DNA damage, with an emphasis on p53's role in DNA repair. We summarize data demonstrating that p53, through its various biochemical activities and via its ability to interact with components of the repair and recombination machinery, actively participates in various processes of DNA repair and DNA recombination. An important aspect in evaluating p53 functions arises from the finding that the p53 core domain harbors two mutually exclusive biochemical activities, sequence-specific DNA binding, required for its transactivation function, and 3'->5' exonuclease activity, possibly involved in various aspects of DNA repair. As modifications of p53 that lead to activation of its sequence-specific DNA-binding activity result in inactivation of its 3'-> 5' exonuclease activity, we propose that p53 exerts its functions as a 'guardian of the genome' at various levels: in its non-induced state, p53 should not be regarded as a non-functional protein, but might be actively involved in prevention and repair of endogenous DNA damage, for example via its exonuclease activity. Upon induction through exogenous DNA damage, p53 will exert its well-documented functions as a superior response element in various types of cellular stress. The dual role model for p53 in maintaining genomic integrity significantly enhances p53's possibilities as a guardian of the genome.

Animals↗
PubMed2006

The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability.

The BRCA1 and BRCA2 proteins are important in maintaining genomic stability by promoting efficient and precise repair of double-strand breaks. The main role of BRCA2 appears to involve regulating the function of RAD51 in the repair by homologous recombination. BRCA1 has a broader role upstream of BRCA2, participating in various cellular processes in response to DNA damage. The DNA repair defect associated with mutations in BRCA1 or BRCA2 could be exploited to develop new targeted therapeutic approaches for cancer occurring in mutation carriers.

BRCA1 Protein↗
PubMed2005

Roles of the Bloom's syndrome helicase in the maintenance of genome stability.

The RecQ family of DNA helicases is highly conserved in evolution from bacteria to humans. Of the five known human RecQ family members, three (BLM, WRN and RECQ4, which cause Bloom's syndrome, Werner's syndrome and Rothmund-Thomson syndrome respectively) are mutated in distinct clinical disorders associated with cancer predisposition and/or premature aging. BLM forms part of a multienzyme complex including topoisomerase IIIalpha, replication protein A and a newly identified factor called BLAP75. Together, these proteins play a role in the resolution of DNA structures that arise during the process of homologous recombination repair. In the absence of BLM, cells show genomic instability and a high incidence of sister-chromatid exchanges. In addition to a DNA structure-specific helicase activity, BLM also catalyses Holliday-junction branch migration and the annealing of complementary single-stranded DNA molecules.

Adenosine Triphosphatases↗
PubMed2002

Caenorhabditis elegans DNA mismatch repair gene msh-2 is required for microsatellite stability and maintenance of genome integrity.

Mismatch repair genes are important in maintaining the fidelity of DNA replication. To determine the function of the Caenorhabditis elegans homologue of the MSH2 mismatch repair gene (msh-2), we isolated a strain of C. elegans with an insertion of the transposable element Tc1 within msh-2. Early-passage msh-2 mutants were similar to wild-type worms with regard to lifespan and meiotic chromosome segregation but had slightly reduced fertility. The mutant worms had reduced DNA damage-induced germ-line apoptosis after genotoxic stress. The msh-2 mutants also had elevated levels of microsatellite instability and increased rates of reversion of the dominant unc-58(e665) mutation. In addition, serially passaged cultures of msh-2 worms died out much more quickly than those of wild-type worms. These results demonstrate that msh-2 function in C. elegans is important in regulating both short- and long-term genomic stability.

Alleles↗
PubMed2004

Regulation of cyclin-dependent kinase activity during mitotic exit and maintenance of genome stability by p21, p27, and p107.

To study the regulation of cyclin-dependent kinase (CDK) activity during mitotic exit in mammalian cells, we constructed murine cell lines that constitutively express a stabilized mutant of cyclin A (cyclin A47). Even though cyclin A47 was expressed throughout mitosis and in G1 cells, its associated CDK activity was inactivated after the transition from metaphase to anaphase. Cyclin A47 associated with both p21 and p27 during mitotic exit, implicating these proteins in CDK inactivation. However, cyclin A47 was fully inhibited during the M-to-G1 transition in p21(-/-) p27(-/-) fibroblasts. Also, the CDKs associated with cyclin A47 were not inactivated by phosphorylation at tyrosines. The protein responsible for CDK inactivation during mitotic exit in p21/p27 null cells was the Rb family member, p107. p107 bound to cyclin A47 when p21 and p27 were absent, and cyclin A47-CDK activity was not inactivated during the M-to-G1 transition in p21(-/-) p27(-/-) p107(-/-) null fibroblasts. Enforced expression of cyclin A in cells lacking all three CDK inhibitors induced rapid tetraploidization, indicative of mitotic failure/endoreduplication. We concluded that cyclin proteolysis and CDK inhibitors constitute redundant pathways that control cyclin A-CDK activity during mitotic exit in mammalian cells and that loss of these pathways can cause genetic instability.

3T3 Cells↗
PubMed2003

Saccharomyces cerevisiae chromatin-assembly factors that act during DNA replication function in the maintenance of genome stability.

Some spontaneous gross chromosomal rearrangements (GCRs) seem to result from DNA-replication errors. The chromatin-assembly factor I (CAF-I) and replication-coupling assembly factor (RCAF) complexes function in chromatin assembly during DNA replication and repair and could play a role in maintaining genome stability. Inactivation of CAF-I or RCAF increased the rate of accumulating different types of GCRs including translocations and deletion of chromosome arms with associated de novo telomere addition. Inactivation of CAF-I seems to cause damage that activates the DNA-damage checkpoints, whereas inactivation of RCAF seems to cause damage that activates the DNA-damage and replication checkpoints. Both defects result in increased genome instability that is normally suppressed by these checkpoints, RAD52-dependent recombination, and PIF1-dependent inhibition of de novo telomere addition. Treatment of CAF-I- or RCAF-defective cells with methyl methanesulfonate increased the induction of GCRs compared with that seen for a wild-type strain. These results indicate that coupling of chromatin assembly to DNA replication and DNA repair is critical to maintaining genome stability.

Chromatin Assembly Factor-1↗
PubMed2002

RAD18 and RAD54 cooperatively contribute to maintenance of genomic stability in vertebrate cells.

Translesion DNA synthesis (TLS) and homologous DNA recombination (HR) are two major pathways that account for survival after post-replicational DNA damage. TLS functions by filling gaps on a daughter strand that remain after DNA replication caused by damage on the mother strand, while HR can repair gaps and breaks using the intact sister chromatid as a template. The RAD18 gene, which is conserved from lower eukaryotes to vertebrates, is essential for TLS in Saccharomyces cerevisiae. To investigate the role of RAD18, we disrupted RAD18 by gene targeting in the chicken B-lymphocyte line DT40. RAD18(-/-) cells are sensitive to various DNA-damaging agents including ultraviolet light and the cross-linking agent cisplatin, consistent with its role in TLS. Interestingly, elevated sister chromatid exchange, which reflects HR- mediated post-replicational repair, was observed in RAD18(-/-) cells during the cell cycle. Strikingly, double mutants of RAD18 and RAD54, a gene involved in HR, are synthetic lethal, although the single mutant in either gene can proliferate with nearly normal kinetics. These data suggest that RAD18 plays an essential role in maintaining chromosomal DNA in cooperation with the RAD54-dependent DNA repair pathway.

Amino Acid Sequence↗
PubMed2005

DNA repair mechanisms in plants: crucial sensors and effectors for the maintenance of genome integrity.

As obligate phototrophs, plants harness energy from sunlight to split water, producing oxygen and reducing power. This lifestyle exposes plants to particularly high levels of genotoxic stress that threatens genomic integrity, leading to mutation, developmental arrest and cell death. Plants, which with algae are the only photosynthetic eukaryotes, have evolved very effective pathways for DNA damage signalling and repair, and this review summarises our current understanding of these processes in the responses of plants to genotoxic stress. We also identify how the use of new and emerging technologies can complement established physiological and ecological studies to progress the application of this knowledge in biotechnology.

Base Pair Mismatch↗
PubMed1995

Insulin-like growth factor II in uterine smooth-muscle tumors: maintenance of genomic imprinting in leiomyomata and loss of imprinting in leiomyosarcomata.

Uterine leiomyosarcomata, malignant smooth-muscle tumors that may arise from existing leiomyomata or directly from the myometrium, have been shown to oversecrete insulin-like growth factor II (IGF-II). It has been shown recently that the IGF-II gene (IGF2) is maternally imprinted in both mice and humans. Only the paternal allele of IGF2 is usually expressed, except in adult liver and in the central nervous system in which biallelic expression is seen. Recently, loss of IGF2 imprinting has been reported in Wilms' tumor and in several other malignancies, and it has been suggested that biallelic expression of the gene leads to overexpression of IGF-II peptide and increased mitogenic activity. Using the ApaI restriction enzyme polymorphism in exon 9 of IGF2, we examined the expression of IGF2 in five informative uterine leiomyosarcomata and found that IGF2 was expressed biallelically in two tumors. In contrast, five samples of normal myometrium and six informative benign uterine leiomyomata showed monoallelic expression of IGF2. The incidence of heterozygosity at this locus was markedly lower in patients with leiomyosarcoma (6%) than in the healthy population (42% heterozygous; P < 0.01). H19, a gene that is imprinted in normal tissues, was expressed monoallelically in all informative normal and neoplastic uterine tumors. In contrast, the IGF-II receptor gene was expressed from both alleles in all tissues examined, confirming the finding that the human IGF-II receptor gene is not imprinted in humans. This study provides further evidence that relaxation of IGF2 genomic imprinting occurs not only in childhood tumors but also in adult-onset tumors, and it suggests a novel epigenetic mechanism for oncogenesis throughout life.

Base Sequence↗
PubMed2005

The human Rothmund-Thomson syndrome gene product, RECQL4, localizes to distinct nuclear foci that coincide with proteins involved in the maintenance of genome stability.

Rothmund-Thomson syndrome (RTS) is a human genetic disorder characterized by genome instability, cancer susceptibility and premature aging. The gene defective in a subset of RTS cases, RECQL4, encodes a member of the RecQ family of DNA helicases. To better define the function of the RECQL4 protein, we have determined its subcellular localization. We have raised antibodies against the N- and C-terminal parts of RECQL4 and could show that in various human cells endogenous RECQL4 forms discrete nuclear foci that colocalize with promyelotic leukaemia protein (PML). The number of foci and their colocalization with PML does not significantly change after induction of different types of DNA damages. Silencing of RECQL4 expression by siRNA causes a significant reduction in RECQL4 nuclear foci formation. Furthermore, we demonstrate that RECQL4 foci coincide with foci formed by human Rad51 and regions of single-stranded DNA after induction of DNA double-strand breaks. In agreement with this, we also show that RECQL4 and Rad51 form a complex in human cells. Our findings suggest a role for RECQL4 in the repair of DNA double-strand breaks by homologous recombination and shed new light onto RECQL4's function in human cells.

Adenosine Triphosphatases↗
PubMed2004

Mating within the meiotic tetrad and the maintenance of genomic heterozygosity.

Mating among the products of a single meiosis (automixis or meiotic parthenogenesis) is found in diverse groups of plant, animal, and fungal taxa. Restoration of the diploid stage is often strictly controlled and brings together products separated at the first meiotic division. Despite apparent similarities to diploid selfing, the theoretical prediction is that heterozygosity should be maintained on all chromosomes when it is linked to the centromeres and thus also segregates at the first meiotic division. Using the fungus Microbotryum, we directly test this prediction by linear tetrad analysis. The patterns of meiotic segregation for chromosome size variation (electrophoretic karyotypes) and PCR products (AFLP procedures) were determined for Microbotryum lineages native to North America and Europe. Our data reveal a surprisingly dynamic genome that is rich in heterozygosity and where size-dimorphic autosomes are common. The genetic variation agrees with the prediction of centromere-linked heterozygosity. This was observed to the greatest extent in the lineage of Microbotryum native to North America where there was consistent first-division segregation and independent assortment of multiple linkage groups. The data also show properties that distinguish the fungal sex chromosomes from the autosomes in both lineages of Microbotryum. We describe a scenario where the mating system of automixis with first-division restitution is the result of feedback mechanisms to control exposure of genetic load.

Basidiomycota↗
PubMed2006

Role of the retinoblastoma tumor suppressor in the maintenance of genome integrity.

The retinoblastoma tumor suppressor (RB) is functionally inactivated at high frequency in human cancers. Based on the role of RB as a negative regulator of cell cycle this event would be expected to contribute to deregulated proliferation. However, evidence suggests that loss of RB not only mediates aberrant proliferation, but compromises the fidelity of cell cycle transitions leading to a breakdown in genome integrity. This review is focused on the mechanisms underlying this facet of RB function and the contribution of this process to tumorigenesis.

Animals↗