Cell division: Genome maintenance.
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Animals↗
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ATM and genome maintenance: defining its role in breast cancer susceptibility.
The ATM gene is mutated in ataxia-telangiectasia (A-T), a genetic instability syndrome characterized by increased cancer risk, as well as other features. Recent studies have shown that the ATM protein kinase plays a critical role in maintaining genome integrity by activating a biochemical chain reaction that in turn leads to cell cycle checkpoint activation and repair of DNA damage. ATM targets include well-known tumor suppressor genes such as p53 and BRCA1, both of which play an important role in predisposition to breast cancer. Studies of A-T families have consistently reported an increased risk of breast cancer in women with one mutated ATM gene, but so far an increased frequency of ATM mutations has not been found in women with breast cancer. Some specific missense and protein truncating variants of ATM have been reported to confer increased breast cancer risk, but the magnitude of this risk remains uncertain. A more comprehensive analysis of ATM is needed in large case-control studies, and in multiple-case breast cancer families.
Ataxia Telangiectasia↗
The N-terminal, putative, mitochondrial targeting domain of the mitochondrial genome maintenance protein (MGM1) in yeast is homologous to the bacterial ribonuclease inhibitor, barstar.
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Amino Acid Sequence↗
Genome maintenance and mutagenesis in embryonic stem cells.
Widespread loss of heterozygosity (LOH) in cancer cells is often thought to result from chromosomal instability caused by mutations affecting DNA repair/genome maintenance; however, the origin of LOH in most tumors is unknown. In a recent study, we examined the ability of carcinogenic agents to induce LOH in diploid mouse embryo-derived stem (ES) cells. Brief exposures to nontoxic levels of several carcinogens stimulated genome-wide LOH, with maximum per-gene frequencies approaching one percent. These results suggest that LOH contributes significantly to the carcinogenicity of a variety of mutagens, and that genome-wide LOH may result from prior exposure to genotoxic agents rather than from a state of chromosomal instability during the carcinogenic process. Mechanisms in stem cells that influence carcinogen-induced LOH are likely to play central roles in the etiology of nonhereditary cancers that often arise after extensive carcinogen exposures.
Animals↗
Cancer and aging: the importance of telomeres in genome maintenance.
Telomeres are the specialized DNA-protein structures that cap the ends of linear chromosomes, thereby protecting them from degradation and fusion by cellular DNA repair processes. In vertebrate cells, telomeres consist of several kilobase pairs of DNA having the sequence TTAGGG, a few hundred base pairs of single-stranded DNA at the 3' end of the telomeric DNA tract, and a host of proteins that organize the telomeric double and single-stranded DNA into a protective structure. Functional telomeres are essential for maintaining the integrity and stability of genomes. When combined with loss of cell cycle checkpoint controls, telomere dysfunction can lead to genomic instability, a common cause and hallmark of cancer. Consequently, normal mammalian cells respond to dysfunctional telomeres by undergoing apoptosis (programmed cell death) or cellular senescence (permanent cell cycle arrest), two cellular tumor suppressor mechanisms. These tumor suppressor mechanisms are potent suppressors of cancer, but recent evidence suggests that they can antagonistically also contribute to aging phenotypes. Here, we review what is known about the structure and function of telomeres in mammalian cells, particularly human cells, and how telomere dysfunction may arise and contribute to cancer and aging phenotypes.
Aging↗
Mechanisms of genome maintenance and rearrangement: current research and recent advances in DNA repair and recombination.
The topics of the talks at the annual DNA Repair Network Meeting at City University, London were as usual wide-ranging and provided an absorbing programme. Covered in the 17 talks were the autoproteolysis of O(6)-methylguanine DNA alkyltransferase in Escherichia coli; identification of new intermediates in meiotic recombination in Saccharomyces cerevisiae; the SMC (structural maintenance of chromosomes) family of proteins in Schizosaccharomyces pombe; transposition and V(D)J recombination; mammalian Rad51 foci formation in Rad54, Rad52, XRCC2 and XRCC3 mutants; biochemical analysis of DNA-PK, ATM (ataxia telangiectasia mutated) and ATR (AT related); other human DNA repair deficiencies and their incidence, including xeroderma pigmentosum and a new DNA ligase IV-deficient patient, and back, once again, to alkyltransferase, this time in humans and its manipulation for engineering drug resistance in bone marrow for cancer treatment.
Animals↗
Structure meets function--centrosomes, genome maintenance and the DNA damage response.
Centrosomes are cytoplasmic organelles playing a fundamental role in organizing both the interphase cytoskeleton and the bipolar mitotic spindle. In addition, the centrosome has recently come into focus as part of the network that integrates cell cycle arrest and repair signals in response to genotoxic stress--the DNA damage response. One important mediator of this response, the checkpoint kinase Chk1, has been shown to negatively regulate the G(2)/M transition via its centrosomal localization. Moreover, there is growing evidence that a centrosome inactivation checkpoint exists, which utilizes DNA damage-induced centrosome fragmentation or amplification to provoke a "mitotic catastrophe" and eliminate damaged cells. Candidate regulators of this centrosomal checkpoint include the checkpoint kinase Chk2 and its upstream regulators ATM and ATR. In addition, a growing number of other proteins have been implicated in centrosomal regulation of the DNA damage response, e.g. the tumor suppressor p53, the breast cancer susceptibility gene product BRCA1 and mitotic regulators such as Aurora A, Nek2 and the Polo-like kinases Plk1 and Plk3. However, many missing links and discrepancies between different model systems remain.
Animals↗
Analysis of the functional domains of the mismatch repair homologue Msh1p and its role in mitochondrial genome maintenance.
Mitochondrial DNA (mtDNA) repair occurs in all eukaryotic organisms and is essential for the maintenance of mitochondrial function. Evidence from both humans and yeast suggests that mismatch repair is one of the pathways that functions in overall mtDNA stability. In the mitochondria of the yeast Saccharomyces cerevisiae, the presence of a homologue to the bacterial MutS mismatch repair protein, MSH1, has long been known to be essential for mitochondrial function. The mechanisms for which it is essential are unclear, however. Here, we analyze the effects of two point mutations, msh1-F105A and msh1-G776D, both predicted to be defective in mismatch repair; and we show that they are both able to maintain partial mitochondrial function. Moreover, there are significant differences in the severity of mitochondrial disruption between the two mutants that suggest multiple roles for Msh1p in addition to mismatch repair. Our overall findings suggest that these additional predicted functions of Msh1p, including recombination surveillance and heteroduplex rejection, may be primarily responsible for its essential role in mtDNA stability.
Amino Acid Sequence↗
The Fanconi anemia pathway of genomic maintenance.
Fanconi anemia (FA), a recessive syndrome with both autosomal and X-linked inheritance, features diverse clinical symptoms, such as progressive bone marrow failure, hypersensitivity to DNA cross-linking agents, chromosomal instability and susceptibility to cancer. At least 12 genetic subtypes have been described (FA-A, B, C, D1, D2, E, F, G, I, J, L, M) and all except FA-I have been linked to a distinct gene. Most FA proteins form a complex that activates the FANCD2 protein via monoubiquitination, while FANCJ and FANCD1/BRCA2 function downstream of this step. The FA proteins typically lack functional domains, except for FANCJ/BRIP1 and FANCM, which are DNA helicases, and FANCL, which is probably an E3 ubiquitin conjugating enzyme. Based on the hypersensitivity to cross-linking agents, the FA proteins are thought to function in the repair of DNA interstrand cross-links, which block the progression of DNA replication forks. Here we present a hypothetical model, which not only describes the assembly of the FA pathway, but also positions this pathway in the broader context of DNA cross-link repair. Finally, the possible role for the FA pathway, in particular FANCF and FANCB, in the origin of sporadic cancer is discussed.
Animals↗
Delineating the requirements for spontaneous DNA damage resistance pathways in genome maintenance and viability in Saccharomyces cerevisiae.
Cellular metabolic processes constantly generate reactive species that damage DNA. To counteract this relentless assault, cells have developed multiple pathways to resist damage. The base excision repair (BER) and nucleotide excision repair (NER) pathways remove damage whereas the recombination (REC) and postreplication repair (PRR) pathways bypass the damage, allowing deferred removal. Genetic studies in yeast indicate that these pathways can process a common spontaneous lesion(s), with mutational inactivation of any pathway increasing the burden on the remaining pathways. In this study, we examine the consequences of simultaneously compromising three or more of these pathways. Although the presence of a functional BER pathway alone is able to support haploid growth, retention of the NER, REC, or PRR pathway alone is not, indicating that BER is the key damage resistance pathway in yeast and may be responsible for the removal of the majority of either spontaneous DNA damage or specifically those lesions that are potentially lethal. In the diploid state, functional BER, NER, or REC alone can support growth, while PRR alone is insufficient for growth. In diploids, the presence of PRR alone may confer a lethal mutation load or, alternatively, PRR alone may be insufficient to deal with potentially lethal, replication-blocking lesions.
Alleles↗
Normal mitochondrial structure and genome maintenance in yeast requires the dynamin-like product of the MGM1 gene.
The isolation and characterization of MGM1, an yeast gene with homology to members of the dynamin gene family, is described. The MGM1 gene is located on the right arm of chromosome XV between STE4 and PTP2. Sequence analysis revealed a single open reading frame of 902 residues capable of encoding a protein with an approximate molecular mass of 101 kDa. Loss of MGM1 resulted in slow growth on rich medium, failure to grow on non-fermentable carbon sources, and loss of mitochondrial DNA. The mitochondria also appeared abnormal when visualized with an antibody to a mitochondrial-matrix marker. MGM1 encodes a dynamin-like protein involved in the propagation of functional mitochondria in yeast.
Base Sequence↗
The impact energy metabolism and genome maintenance have on longevity and senescence: lessons from yeast to mammals.
The phenomenon that caloric restriction increases life span in a variety of species from yeast to mice has been the focus of much interest. Recent observations suggest that a protein important for heterochromatin formation, Sir2, is central for caloric restriction-induced longevity in lower organisms. Interestingly, Sir2 is also capable of repairing DNA double-strand breaks by nonhomologous end joining which may be important, along with proteins that repair breaks by recombinational repair, for minimizing the age-related deleterious effects of DNA damage induced by oxygen by-products of metabolism. I propose that competition between these two distinct functions could influence longevity and the onset of senescence. In addition, sequence and functional similarities between Sir2 and other chromatin metabolism proteins present the possibility that genetic components for longevity and senescence are conserved from yeast to mammals.
Aging↗
A multifaceted role for ATM in genome maintenance.
The pleiotropic nature of the clinical phenotypes of patients with ataxia-telangiectasia (A-T)--which encompass cerebellar degeneration (leading to ataxia), gonadal atrophy, and cancer predisposition--suggests multiple functions of the gene responsible for the disease. The ataxia-telangiectasia mutated gene product (ATM), whose loss of function is responsible for ataxia-telangiectasia, is a protein kinase that interacts with several substrates and is implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, cell-cycle control and telomere maintenance. This review focuses on the critical roles that ATM appears to play in cell-cycle checkpoints, DNA repair, telomere metabolism and oxidative stress, indicating how defects in these processes might lead to ataxia-telangiectasia.
Ataxia Telangiectasia↗
Involvement of genes of genome maintenance in the regulation of phase variation frequencies in Neisseria meningitidis.
In Neisseria meningitidis, the reversible expression of surface antigens, i.e. phase variation, results from changes within repeated simple sequence motifs located in coding or promoter regions of the genes involved in their biosynthesis. The mutation rates of these simple sequences, which have a major influence on the generation of phenotypic diversity, can affect the fitness of the population. The aim of the present study was to investigate the involvement of genetic factors involved (mutS and dam) and not yet analysed (drg and dinB) in the regulation of phase variation frequencies of genes associated with a variety of repeat tracts. The frequency of frameshifts occurring in the polycytidine (polyC) tracts associated with siaD, spr and lgtG and in the tetranucleotide (TAAA) repeat tract associated with nadA was determined by colony immunoblotting or using the lacZ gene as a reporter. Inactivation of mutS increased the frequency of phase variation of genes presenting homopolymeric tracts of diverse length. Overexpression of dinB enhanced the instability of the homopolymeric tract associated with siaD. Investigation of the dam locus in a population of genetically distinct N. meningitidis strains revealed that 27 % of strains associated with invasive disease contained the dam gene. In all strains where a Dam function was absent, the drg gene had been inserted into the dam locus. Disruption of dam and drg in strains representative of each genotype, i.e. dam(+)/drg and dam/drg(+), did not modify phase variation frequencies. In contrast to the effects of certain genes on homopolymeric tracts, none of the genetic factors investigated affected the stability of tetranucleotide repeat tracts.
Adenosine Triphosphatases↗
MutY and MutY homologs (MYH) in genome maintenance.
The base excision repair carried out by bacterial MutY DNA glycosylase and eukaryotic MutY homolog (MYH) is responsible for removing adenines misincorporated into DNA opposite G and 7,8-dihydro-8-oxo-guanines (8-oxoG); thereby preventing G:C to T:A mutations. Escherichia coli MutY (EcMutY) can also remove adenines from A/C and A/5-hydroxyuracil and can remove guanines from G/8-oxoG mismatches at reduced rates. Thus, MutY has a minor role in reducing the mutagenic effects on G:C to A:T transitions and G:C to C:G transversions. The eukaryotic MYH can excise adenines misincorporated opposite GO, G, or C; remove 2-hydroxyadenines mispaired with A,G, and GO; excise G from G/GO mismatch weakly, thereby preventing G:C to T:A transversions. The in vitro and in vivo activities of MYH can be modulated by several proteins including apurinic/apyrimidinic endonuclease (APE1), proliferating cell nuclear antigen (PCNA), and mismatch recognition enzymes MSH2/MSH6. Recently, MYH has been shown to associate with the checkpoint proteins, Rad9, Rad1, and Hus1 (referred as the 9-1-1 complex). Thus, MYH-mediated base excision repair is coordinated with mismatch repair, DNA replication, cell-cycle progression, and DNA-damage checkpoints. Biallelic germ-line mutations in the human MYH gene are associated with recessive inheritance of multiple colorectal adenomas and carcinoma. MYH mutations can cause G:C to T:A mutations of the adenomatous polyposis coli (APC), K-ras, and other genes that control cellular proliferation in the colon.
Animals↗
Lack of a mechanism for faithful partition and maintenance of the KSHV genome.
Kaposi's sarcoma-associated herpesvirus (KSHV) is a causative agent for some tumors. The virus establishes latency in infected cells, where its genomes are often present as episomes and replicate in a cell-cycle-dependent manner, apparently maintaining the same copy number. LANA and TR are key KSHV replication factors, and we hypothesized that they also function in viral genome maintenance. We cloned a bacmid containing the viral TR region from PEL cells and tested whether TR with LANA were sufficient for viral genome maintenance. However, neither the TR region nor even the full KSHV genome cloned into a bacmid were maintained in cultured cells, except when they were grown under selective pressure. Thus, no specific viral mechanism for the faithful partitioning and maintenance of the KSHV genome is likely to exist. KSHV might confer a positive growth effect on infected PEL cells, but not on immortalized or transformed cells previously uninfected by KSHV.
Antigens, Viral↗
MGM101, a nuclear gene involved in maintenance of the mitochondrial genome in Saccharomyces cerevisiae.
A nuclear mutation, mgm101, results in temperature sensitive loss of mitochondrial DNA (mtDNA) in the yeast Saccharomyces cerevisiae. The corresponding gene, MGM101, was isolated from a genomic DNA library by complementation. Sequence analysis shows that MGM101 encodes a positively charged protein of 269 amino acids with a calculated molecular weight of 30 kDa. This analysis also reveals that MGM101 is adjacent to the ribosomal protein gene RPS7A on chromosome X and hybridization indicates it occurs in single copy. Creation of a null mutant by targeted disruption showed that the gene has no essential cellular function, aside from its participation in mitochondrial genome maintenance. As no counterpart has been identified in databases it is a novel protein whose role has yet to be determined. Expression of MGM101 is low on glucose medium but on galactose there is a two-fold increase in the level of the transcript.
Amino Acid Sequence↗
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↗