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PubMed1998

DNA repair in Mycobacterium tuberculosis. What have we learnt from the genome sequence?

The genome sequence of Mycobacterium tuberculosis was analysed by searching for homologues of genes known to be involved in the reversal or repair of DNA damage in Escherichia coli and related organisms. Genes necessary to perform nucleotide excision repair (NER), base excision repair (BER), recombination, and SOS repair and mutagenesis were identified. In particular, all of the genes known to be directly involved in the repair of oxidative and alkylative damage are present in M. tuberculosis. In contrast, we failed to identify homologues of genes involved in mismatch repair. This finding has potentially significant implications with respect to genome stability, strain variability at repeat loci and the emergence of chromosomally encoded drug resistance mutations.

DNA Damage↗
PubMed2006

The double life of UPF1 in RNA and DNA stability pathways.

The DNA and RNA helicase UPF1 is well known for its central role in Nonsense Mediated RNA Decay (NMD), which promotes degradation of mRNAs containing premature stop codons. However, we have recently demonstrated that human UPF1 is also essential for DNA replication and S phase progression. This function appears to be independent of NMD, which is not required for cell cycle progression. UPF1 physically interacts with the replicative DNA polymerase delta and it associates with chromatin during S phase and upon DNA damage in an ATR-dependent manner. Intriguingly, the human NMD-kinase SMG1 is also involved in genome stability pathways and the human NMD-factor EST1A/SMG6 is telomerase-associated and has been implicated in telomere maintenance. Here we review the recent findings, which uncovered the direct roles of UPF1 and other NMD-factors in DNA replication and genome maintenance pathways and suggest functional connections between RNA and DNA metabolism.

DNA↗
PubMed1999

Comparison of DNA damage in plants as measured by single cell gel electrophoresis and somatic leaf mutations induced by monofunctional alkylating agents.

The use of single cell gel electrophoresis (SCGE) has recently been applied to plant systems. We optimized the experimental conditions for SCGE analysis using nuclei isolated from different tissues of intact plants. Concentration-response curves of genomic DNA migration were analyzed in intact plants treated with the monofunctional alkylating agents ethyl methanesulfonate (EMS), methyl methanesulfonate (MMS), N-ethyl-N-nitrosourea (ENU), and N-methyl-N-nitrosourea (MNU). These data were used to calibrate SCGE tail moment values to induced somatic mutation in plant leaves. We used a genotoxicity index to compare genomic DNA damage and the induction of somatic mutation in the leaf tissues. The rank order of the genotoxic potency of these alkylating agents assayed by SCGE was MNU >> MMS > ENU > EMS. The rank order for the mutagenic potency of these agents was MNU >> ENU congruent with MMS > EMS. The data demonstrate the utility of SCGE analysis in plant systems. The use of SCGE will permit a larger range of plants for use as in situ environmental monitors. Also, this approach may be used to search for crop plant germplasm accessions with enhanced genomic stability. We investigated whether the intragenomic distributions of DNA damage induced by these alkylating agents were uniform and random. When a plot of the ratio of the %tail DNA and tail length versus the concentration of the test mutagen was generated, the induced SCGE data deviated from a random distribution of genomic DNA damage.

Alkylating Agents↗
PubMed2026

Helitrons are enriched in lichenized fungi with long generation lengths and small distribution sizes.

Transposable elements have the potential to drive genome evolution by introducing mutations and causing structural instability and chromosomal rearrangements, particularly under conditions like environmental or genetic stress. In this study, we generated 18 new long-read-based metagenomically assembled reference genomes for lichenized fungi, which form obligate mutualistic symbioses with algae or cyanobacteria. We used the new genomes and 10 publicly available genomes to investigate the relationships between species traits (i.e. dominant reproductive mode, distribution size, and generation length) and the abundance and spatial distribution of transposable elements using a phylogenetic comparative framework. We found that species with smaller distribution sizes and longer generation lengths had a higher genomic DNA transposon load. Specifically, their genomes were enriched with Rolling Circle transposons, which contradict previous research that has identified high proportions of retrotransposons in rare species. Disproportionate distributions of transposable elements in rare and range-restricted species may disrupt genomic stability, decrease fitness, and be reflective of species experiencing a greater degree of stress. Conversely, greater transposable element activity may be an important source of novel genetic diversity in isolated populations with limited gene flow. Further research is needed to understand the potential mechanisms driving transposable element proliferation in rare species' genomes and if transposable element content is predictive of increased extinction risk.

DNA Transposable Elements↗
PubMed1999

Characterization of the human Rad51 genomic locus and examination of tumors with 15q14-15 loss of heterozygosity (LOH).

Human Rad51 (hRad51) has been found to be associated with BRCA1, BRCA2, and p53 either directly or indirectly and is one of at least eight human genes that are members of the Escherichia coli RecA/Saccharomyces cerevisiae Rad51 family thought to affect genomic stability through DNA recombination/repair processes. While inactivation of DNA mismatch repair clearly leads to instability of repeated sequences and to an increased risk for tumorigenesis, such a parallel for the RecA family members has not been reported. Recently, a high frequency of loss of heterozygosity at chromosome 15q14-15, near the genomic region containing hRad51, has been reported in human tumors (W. Wick et al., Oncogene, 12: 973-978, 1996). To determine whether hRad51 inactivation may be involved in the etiology of these tumors, we have characterized the hRad51 genetic locus and mapped it to chromosome 15q14-15 within the central region of loss of heterozygosity. However, single-strand conformational polymorphism analysis and direct sequencing of tumors did not reveal any mutations in the hRad51 coding sequence or intron/exon boundaries. We also examined the DNA methylation status of a CpG-rich region in the putative hRad51 promoter region. No indication of hypermethylation was found. These results suggest that hRad51 is not a tumor suppressor because it is either an essential gene, redundant gene and/or independent of the BRCA1/BRCA2 tumor suppressor pathway(s).

5' Untranslated Regions↗
PubMedDate not supplied

The DNA double-strand break response pathway: becoming more BRCAish than ever.

Breast carcinoma is the leading cause of cancer incidence, and second in cancer mortality to lung cancer, in women of the Western hemisphere. Germ line mutations in the breast cancer susceptibility gene, BRCA1, is responsible for half of all cases of hereditary breast cancer, which constitutes about 5-10% of all cases of breast cancer. Current hypothesis has ascribed a role for Brca1 in maintaining genomic stability, through its involvement in cellular response pathway to the DNA double-strand breaks (DSB). DNA DSB, which are the most deleterious form of DNA damage, are repaired through a series of coordinated steps embedded in a signal transduction pathway that ultimately ensure the elimination of potentially harmful mutations to the genome. This pathway can be crudely divided into a primary and secondary phase. The primary response phase is initiated by sensor proteins that activate transducer protein kinases Atm and Atr, which target downstream effector proteins, such as Chk1 and Chk2, to elicit the secondary response phase. Brca1 has been intimately linked with various aspects of this signaling pathway. However, the precise role of Brca1 in this process remains unclear. In this review, we will provide a simple model in an attempt to clarify the role of Brca1 during cellular response to DNA DSB.

Animals↗
PubMed2006

DNA damage checkpoints and cancer.

DNA damage checkpoint is one of the surveillance systems to maintain genomic integrity. Checkpoint systems sense the DNA damage and execute cell cycle arrest through inhibiting the activity of cell cycle regulators. This pathway is essential for the maintenance of genome stability and prevention of tumor development. Recent studies have showed that the cellular responses towards DNA damage, such as cell cycle arrest, DNA repair, chromatin remodeling, and apoptosis are well coordinated. Here we describe the molecular mechanisms of checkpoint activation in response to DNA damage and the correlation between checkpoint gene mutation and genomic instability.

Animals↗
PubMed2006

Improved repeat identification and masking in Dipterans.

Repetitive sequences are a major constituent of many eukaryote genomes and play roles in gene regulation, chromosome inheritance, nuclear architecture, and genome stability. The identification of repetitive elements has traditionally relied on in-depth, manual curation and computational determination of close relatives based on DNA identity. However, the rapid divergence of repetitive sequence has made identification of repeats by DNA identity difficult even in closely related species. Hence, the presence of unidentified repeats in genome sequences affects the quality of gene annotations and annotation-dependent analyses (e.g. microarray analyses). We have developed an enhanced repeat identification pipeline using two approaches. First, the de novo repeat finding program PILER-DF was used to identify interspersed repetitive elements in several recently finished Dipteran genomes. Repeats were classified, when possible, according to their similarity to known elements described in Repbase and GenBank, and also screened against annotated genes as one means of eliminating false positives. Second, we used a new program called RepeatRunner, which integrates results from both RepeatMasker nucleotide searches and protein searches using BLASTX. Using RepeatRunner with PILER-DF predictions, we masked repeats in thirteen Dipteran genomes and conclude that combining PILER-DF and RepeatRunner greatly enhances repeat identification in both well-characterized and un-annotated genomes.

Animals↗
PubMed2003

Dna2 helicase/nuclease causes replicative fork stalling and double-strand breaks in the ribosomal DNA of Saccharomyces cerevisiae.

We have proposed that faulty processing of arrested replication forks leads to increases in recombination and chromosome instability in Saccharomyces cerevisiae and contributes to the shortened lifespan of dna2 mutants. Now we use the ribosomal DNA locus, which is a good model for all stages of DNA replication, to test this hypothesis. We show directly that DNA replication pausing at the ribosomal DNA replication fork barrier (RFB) is accompanied by the occurrence of double-strand breaks near the RFB. Both pausing and breakage are elevated in the early aging, hypomorphic dna2-2 helicase mutant. Deletion of FOB1, encoding the fork barrier protein, suppresses the elevated pausing and DSB formation, and represses initiation at rDNA ARSs. The dna2-2 mutation is synthetically lethal with deltarrm3, encoding another DNA helicase involved in rDNA replication. It does not appear to be the case that the rDNA is the only determinant of genome stability during the yeast lifespan however since strains carrying deletion of all chromosomal rDNA but with all rDNA supplied on a plasmid, have decreased rather than increased lifespan. We conclude that the replication-associated defects that we can measure in the rDNA are symbolic of similar events occurring either stochastically throughout the genome or at other regions where replication forks move slowly or stall, such as telomeres, centromeres, or replication slow zones.

Adenosine Triphosphatases↗
PubMed2001

Targeting the molecular mechanism of DNA replication.

Genome stability is crucial for the complete maintenance of the cellular pathways that govern the cell cycle. As a result of irregularities in DNA replication occurring throughout the S phase, key genes that regulate cell cycle pathways are damaged, giving rise to single-base mutations and chromosomal aberrations. Thus, the efficient replication of the genome, which depends on a precise temporal and spatial pattern of activation of origins of replication, is greatly impaired. The approach discussed below aims at monitoring the replication pattern and the kinetics of replication throughout the entire genome of living cells. It could shed light on the mechanisms by which drugs act on DNA replication and, moreover, it might assist the discovery and design of novel drugs that inhibit cell proliferation under pathophysiological conditions.

Journal Article↗
PubMed1997

Properties of intraepithelial neoplasia relevant to cancer chemoprevention and to the development of surrogate end points for clinical trials.

Cancer chemoprevention is defined as the prevention of cancer by the administration of diet supplements or drugs. A drug discovery effort should therefore focus on finding agents that will avert the process of intraepithelial neoplasia which precedes invasive cancer. Over 30 agents developed by the chemoprevention program at the National Cancer Institute are being tested against intraepithelial neoplasia of many organ sites in more than 80 clinical trials. Two basic mechanisms underlie the onset and development of intraepithelial neoplasia. First is the development of the two precursor lesions of chronic diffuse epithelial hyperplasia and genomic instability, the latter being produced by "mutator" mutations in genes responsible for genomic stability, by gene copy amplification or loss from DNA breakage-fusion-anaphase-bridge cycles, by unequal sister chromatid exchange, and by accumulation of double minutes. Second is the development of multicentric intraepithelial neoplastic lesions which independently progress through each of the following processes at a continuously accelerating rate: clonal evolution, hyperproliferation, production of genomic structural variants, and apoptosis. Recommended chemoprevention strategies based on these mechanisms are (i) the development of better technology for early diagnosis, (ii) the development of multiple agents that block intralesional proliferation at steps along the signal pathway of mitotic signal transduction and along the signal pathway of synthesis of daughter cell components, (iii) the development of nontoxic anti-inflammatory agents, anitoxidants, antimutagens, and proapoptotics, (iv) the avoidance of "clonal escape" through use of drug combinations, and (v) the use of computer-assisted quantitative image analysis to assay modulation of surrogate end points in chemoprevention clinical trials.

Anticarcinogenic Agents↗
PubMed2003

The Rad27 (Fen-1) nuclease inhibits Ty1 mobility in Saccharomyces cerevisiae.

Although most Ty1 elements in Saccharomyces cerevisiae are competent for retrotransposition, host defense genes can inhibit different steps of the Ty1 life cycle. Here, we demonstrate that Rad27, a structure-specific nuclease that plays an important role in DNA replication and genome stability, inhibits Ty1 at a post-translational level. We have examined the effects of various rad27 mutations on Ty1 element retrotransposition and cDNA recombination, termed Ty1 mobility. The point mutations rad27-G67S, rad27-G240D, and rad27-E158D that cause defects in certain enzymatic activities in vitro result in variable increases in Ty1 mobility, ranging from 4- to 22-fold. The C-terminal frameshift mutation rad27-324 confers the maximum increase in Ty1 mobility (198-fold), unincorporated cDNA, and insertion at preferred target sites. The null mutation differs from the other rad27 alleles by increasing the frequency of multimeric Ty1 insertions and cDNA recombination with a genomic element. The rad27 mutants do not markedly alter the levels of Ty1 RNA or the TyA1-gag protein. However, there is an increase in the stability of unincorporated Ty1 cDNA in rad27-324 and the null mutant. Our results suggest that Rad27 inhibits Ty1 mobility by destabilizing unincorporated Ty1 cDNA and preventing the formation of Ty1 multimers.

Endodeoxyribonucleases↗
PubMed1987

A highly polymorphic region in the X chromosome of Drosophila.

Many cloned regions of the Drosophila genome show minimal variation between strains in overall sequence arrangement. While restriction site polymorphisms occur and the location of transposable elements may vary from one strain to another, such changes appear to be relatively minor variations superimposed on overall genome stability. In contrast to this general situation, we describe here a segment of the X chromosome that is highly polymorphic in four strains of D. melanogaster and in D. simulans. The strains differ in the presence and extent of a short duplication and the presence of repetitive DNA. These results suggest that different regions of the genome may be subject to different evolutionary constraints, with some regions being particularly prone to extensive changes, even within a single species.

Animals↗
PubMed2006

Long inverted repeats in eukaryotic genomes: recombinogenic motifs determine genomic plasticity.

Inverted repeats are unstable motifs in a genome, having a causal relation to fragment rearrangements and recombination events. We have investigated long inverted repeats (LIR) of > 30 bp in length in eukaryotic genomes to assess their contribution to genome stability. An algorithm was first designed for searching for LIRs with < 2 kb internal spacers and >85% identity (degree of homology between repeat copies of a LIR). There are much fewer LIRs in yeast, fruitfly, pufferfish and chicken than in Caenorhabditis elegans, zebrafish, frog and human. However, the high LIR frequencies do not necessarily imply high genome instability because of variant internal spacers and stem lengths and identities. From the collection of identified LIRs, we selected recombinogenic LIRs that had a short internal spacer and a high copy identity and were prone to induce high instability. We found that a relatively high proportion (5-9.8%) of the LIRs in C. elegans, zebrafish and frog were recombinogenic LIRs. In contrast, the proportions in human and mouse LIRs were quite low (0.4-1.1%) basically accounting for long internal spacers. We suggest that C. elegans, zebrafish and frog genomes are unstable in terms of the LIR frequency and the proportion of recombinogenic LIRs. For the other genomes, LIRs most likely have a minor impact.

Algorithms↗
PubMed2026

Folding a broken genome: the versatile roles of cohesin in genome maintenance.

Cohesin is a protein complex that shapes 3D genome organization through two distinct mechanisms. First, cohesin tethers replicated chromatids from DNA replication until mitosis. This process, known as sister chromatid cohesion, ensures accurate chromosome segregation and enables high-fidelity DNA repair through homologous recombination between the sister chromatids. Second, cohesin organizes the genome during interphase by dynamically extruding chromatin loops, structures that have key roles in gene regulation. Recent work has shown that, in addition to the well-established repair functions of sister chromatid cohesion, cohesin-mediated chromatin looping is closely linked to the repair of DNA double-strand breaks - one of the most toxic DNA lesions. In this Review, we discuss the central roles of cohesin in maintaining genome stability, with emphasis on the cellular response to DNA double-strand breaks. We review how dynamic loop structures facilitate signalling of repair events and promote long-range chromatin motions that underpin the repair process. Overall, its dual mode of action - cohesion and loop extrusion - positions cohesin as a central regulator of chromatin architecture and genome maintenance.

Cohesins↗
PubMed2006

MPS1-dependent mitotic BLM phosphorylation is important for chromosome stability.

Spindle assembly checkpoint (SAC) ensures bipolar attachment of chromosomes to the mitotic spindle and is essential for faithful chromosome segregation, thereby preventing chromosome instability (CIN). Genetic evidence suggests a causal link between compromised SAC, CIN, and cancer. Bloom syndrome (BS) is a genetic disorder that predisposes affected individuals to cancer. BS cells exhibit elevated rates of sister chromatid exchange, chromosome breaks, and CIN. The BS gene product, BLM, is a member of the RecQ helicases that are required for maintenance of genome stability. The BLM helicase interacts with proteins involved in DNA replication, recombination, and repair and is required for the repair of stalled-replication forks and in the DNA damage response. Here we present biochemical evidence to suggest a role of BLM phosphorylation during mitosis in maintaining chromosome stability. BLM is associated with the SAC kinase MPS1 and is phosphorylated at S144 in a MPS1-dependent manner. Phosphorylated BLM interacts with polo-like kinase 1, a mitotic kinase that binds to phosphoserine/threonine through its polo-box domain (PBD). Furthermore, BS cells expressing BLM-S144A show normal levels of sister chromatid exchange but fail to maintain the mitotic arrest when SAC is activated and exhibit a broad distribution of chromosome numbers. We propose that MPS1-dependent BLM phosphorylation is important for ensuring accurate chromosome segregation, and its deregulation may contribute to cancer.

Adenosine Triphosphatases↗
PubMed2004

Post-integration stabilization of a transposon vector by terminal sequence deletion in Drosophila melanogaster.

Germline transformation systems for nearly 20 insect species have been derived from transposable elements, allowing the development of transgenic insects for basic and applied studies. These systems use a defective nonautonomous vector that results in stable vector integrations after the disappearance of transiently provided transposase helper plasmid, which is essential to maintain true breeding lines and consistent transgene expression that would otherwise be lost after vector remobilization. The risk of remobilization by an unintended transposase source has so far not been a concern for laboratory studies, but the prospective use of millions of transgenic insects in biocontrol programs will likely increase the risk, therefore making this a critical issue for the ecological safety of field release programs. Here we describe an efficient method that deletes a terminal repeat sequence of a transposon vector after genomic integration. This procedure prevents transposase-mediated remobilization of the other terminal sequence and associated genes, ensuring their genomic stability.

Animals↗
PubMed2001

tef: a mutation that causes telomere fusion and severe genome rearrangements in Drosophila melanogaster.

Telomeres are the stable ends of linear chromosomes in eukaryotes. These complex protein-nucleic acid structures are essential to maintain genomic stability and the integrity of linear chromosomes. We identified a new mutation in Drosophila that causes a high frequency of end-to-end fusions of chromosomes during mitosis and meiosis. Linear chromosomal ends appear to be essential for fusions to take place. These fusions do not resolve, leading to cycles of chromosomal breakage and rejoining and severe genome rearrangements. The gene is essential for normal cell proliferation and mutant tissue shows significant apoptosis. Our analysis suggests that the function encoded by the mutant gene is required to protect the linear ends of chromosomes.

Animals↗