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At least 145 records · Page 8Linked to original sources
PubMed2005

Geminiviruses and RNA silencing.

Geminiviruses are single-stranded circular DNA viruses that cause economically significant diseases in a wide range of crop plants worldwide. In plants, post-transcriptional gene silencing (PTGS) acts as a natural anti-viral defense system and plays a role in genome maintenance and development. During the past decade there has been considerable evidence of PTGS suppression by viruses, which is often required to establish infection in plants. In particular, nuclear-replicating geminiviruses, which have no double-stranded RNA phase in their replication cycle, can induce and suppress the PTGS and become targets for PTGS. Here, we summarize recent developments in determining how these viruses trigger PTGS and how they suppress the induced PTGS, as well as how we can use the system to control these viruses in plants better and manipulate the system to study functional genomics in crop plants.

Geminiviridae↗
PubMed2025

Distinct roles of the two BRCA2 DNA-binding domains in DNA damage repair and replication fork preservation.

Homologous recombination (HR) removes DNA double-strand breaks (DSBs) and preserves stressed DNA replication forks. Successful HR execution requires the tumor suppressor BRCA2, which harbors distinct DNA-binding domains (DBDs): one that possesses three oligonucleotide/oligosaccharide-binding (OB) folds (OB-DBD) and another residing in the C-terminal recombinase binding domain (CTRB-DBD). Here, we employ multi-faceted approaches to delineate the contributions of these domains toward HR and replication fork maintenance. We show that OB-DBD and CTRB-DBD confer single-strand DNA (ssDNA)- and dsDNA-binding capabilities, respectively, and that BRCA2 variants mutated in either domain are impaired in their ability to load the recombinase RAD51 onto ssDNA pre-occupied by RPA. While the CTRB-DBD mutant is modestly affected by DNA break repair, it exhibits a strong defect in the protection of stressed replication forks. In contrast, the OB-DBD is indispensable for both BRCA2 functions. Our study thus defines the unique contributions of the two BRCA2 DBDs in genome maintenance.

BRCA2 Protein↗
PubMed2026

Decoding context-dependent sirtuin pharmacology in cancer: Metabolic-epigenetic switches and precision therapeutic targeting.

Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.

Humans↗
PubMedDate not supplied

Structure and function of RecQ DNA helicases.

RecQ family helicases play important roles in coordinating genome maintenance pathways in living cells. In the absence of functional RecQ proteins, cells exhibit a variety of phenotypes, including increased mitotic recombination, elevated chromosome missegregation, hypersensitivity to DNA-damaging agents, and defects in meiosis. Mutations in three of the five human RecQ family members give rise to genetic disorders associated with a predisposition to cancer and premature aging, highlighting the importance of RecQ proteins and their cellular activities for human health. Current evidence suggests that RecQ proteins act at multiple steps in DNA replication, including stabilization of replication forks and removal of DNA recombination intermediates, in order to maintain genome integrity. The cellular basis of RecQ helicase function may be explained through interactions with multiple components of the DNA replication and recombination machinery. This review focuses on biochemical and structural aspects of the RecQ helicases and how these features relate to their known cellular function, specifically in preventing excessive recombination.

Adenosine Triphosphatases↗
PubMed2005

Poly(ADP-ribosyl)ation by PARP-1: 'PAR-laying' NAD+ into a nuclear signal.

Poly(ADP-ribose) (PAR) and the PAR polymerases (PARPs) that catalyze its synthesis from donor nicotinamide adenine dinucleotide (NAD+) molecules have received considerable attention in the recent literature. Poly(ADP-ribosyl)ation (PARylation) plays diverse roles in many molecular and cellular processes, including DNA damage detection and repair, chromatin modification, transcription, cell death pathways, insulator function, and mitotic apparatus function. These processes are critical for many physiological and pathophysiological outcomes, including genome maintenance, carcinogenesis, aging, inflammation, and neuronal function. This review highlights recent work on the biochemistry, molecular biology, physiology, and pathophysiology of PARylation, focusing on the activity of PARP-1, the most abundantly expressed member of a family of PARP proteins. In addition, connections between nuclear NAD+ metabolism and nuclear signaling through PARP-1 are discussed.

Aging↗
PubMed2005

Multifaceted role of the Saccharomyces cerevisiae Srs2 helicase in homologous recombination regulation.

Homologous recombination (HR) is a major pathway for the elimination of DNA DSBs (double-strand breaks) induced by high-energy radiation and chemicals, or that arise due to endogenous damage and stalled DNA replication forks. If not processed properly, DSBs can lead to cell death, chromosome aberrations and tumorigenesis. Even though HR is important for genome maintenance, it can also interfere with other DNA repair mechanisms and cause gross chromosome rearrangements. In addition, HR can generate DNA or nucleoprotein intermediates that elicit prolonged cell-cycle arrest and sometimes cell death. Genetic analyses in the yeast Saccharomyces cerevisiae have revealed a central role of the Srs2 helicase in preventing untimely HR events and in inhibiting the formation of potentially deleterious DNA structures or nucleoprotein complexes upon DNA replication stress. Paradoxically, efficient repair of DNA DSBs by HR is dependent on Srs2. In this paper, we review recent molecular studies aimed at deciphering the multifaceted role of Srs2 in HR and other cellular processes. These studies have provided critical insights into how HR is regulated in order to preserve genomic integrity and promote cell survival.

Cytoskeleton↗
PubMed2004

Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes.

The papillomavirus E2 protein tethers viral genomes to host mitotic chromosomes to ensure genome maintenance. We have identified the bromodomain protein Brd4 as a major cellular interacting partner of the bovine papillomavirus E2. Brd4 associates with mitotic chromosomes and colocalizes with E2 on mitotic chromosomes. The site of E2 binding maps to the C-terminal domain of Brd4. Expression of this C-terminal Brd4 domain functions in a dominant-negative manner to abrogate the colocalization of E2 with Brd4 on mitotic chromosomes, to block association of the viral episomes with Brd4, and to inhibit BPV-1 DNA-mediated cellular transformation. Brd4 also associates with HPV16 E2, indicating that Brd4 binding may be a shared property of all papillomavirus E2 proteins. The interaction of E2 with Brd4 is required to ensure the tethering of viral genomes to the host mitotic chromosomes for persistence of viral episomes in PV-infected cells.

Adenovirus E2 Proteins↗
PubMedDate not supplied

Molecular diagnosis of pancreatic cancer.

Pancreatic ductal adenocarcinoma is a result of accumulated genetic alterations, including oncogenes such as K-ras, tumor-suppressor genes such as p53, p16 and DPC4 and genome-maintenance genes such as BRCA2, microsatellite instability and telomerase. Recent findings which characterize the molecular genetic profile of the pancreatic cancer have reshaped the nomenclature describing histological progression in pancreatic ductal tumorigenesis. K-ras mutations frequently occur early, whereas changes in the expression and genetic integrity of the p16 gene appear in intermediate lesions, and the inactivation of the p53, DPC4 genes and activation of telomerase occur late in the neoplastic progression. So far K-ras and telomerase activity have been used as molecular markers for the diagnosis of pancreatic carcinoma, whereas p53 and p16 may be a prognostic indicator of pancreatic cancer. Additional tumor-suppressor genes and the related signaling pathway such as ALK-5 are likely to be defined. In addition to the human genome project, these new advances hopefully will accelerate the development of diagnostic and screening techniques for this grave condition.

Cell Differentiation↗
PubMed2004

Rapid accumulation of mutations during seed-to-seed propagation of mismatch-repair-defective Arabidopsis.

During the many cell divisions that precede formation of plant gametes, their apical-meristem and floral antecedents are continually exposed to endogenous and environmental mutagenic threats. Although some deleterious recessive mutations may be eliminated during growth of haploid gametophytes and functionally haploid early embryos ("haplosufficiency quality-checking"), the multiplicity of plant genome-maintenance systems suggests aggressive quality control during prior diploid growth. To test in Arabidopsis a hypothesis that prior mismatch repair (MMR) is paramount in defense of plant genetic fidelity, we propagated in parallel 36 MMR-defective (Atmsh2-1) and 36 wild-type lines. The Atmsh2-1 lines rapidly accumulated a wide variety of mutations: fifth-generation (G5) plants showed abnormalities in morphology and development, fertility, germination efficiency, seed/silique development, and seed set. Only two Atmsh2-1, but all 36 wild-type lines, appeared normal at G5. Analyses of insertion/deletion mutation at six repeat-sequence (microsatellite) loci showed each Atmsh2-1 line to have evolved its own "fingerprint," the results of as many as 10 microsatellite mutations in a single line. Thus, MMR during diploid growth is essential for plant genomic integrity.

Arabidopsis↗
PubMed2006

Molecular pathogenesis of pancreatic cancer.

Pancreatic cancer is fundamentally a disease of inherited and acquired mutations in cancer-related genes. The genes targeted in pancreatic cancer include tumor-suppressor genes (p16/CDKN2A, TP53 and SMAD4), oncogenes (KRAS, BRAF, AKT2, MYB, and AIB1), and genome-maintenance genes (MLH1, MSH2, BRAC2 and other Fanconi anemia genes). An understanding of the cancer-related genes that are altered in pancreatic cancer has a number of clinical applications including genetic counseling for individuals with a family history of cancer, early detection of pancreatic neoplasia, and mechanism-based therapies for patients with advanced disease. This chapter will provide an overview of the molecular pathogenesis of pancreatic cancer with emphasis on clinical applications.

Carcinoma in Situ↗
PubMed1999

Gene silencing in Neurospora crassa requires a protein homologous to RNA-dependent RNA polymerase.

In plants and fungi, the introduction of transgenes can lead to post-transcriptional gene silencing. This phenomenon, in which expression of the transgene and of endogenous genes containing sequences homologous to the transgene can be blocked, is involved in virus resistance and genome maintenance. Transgene-induced gene silencing has been termed quelling in Neurospora crassa and co-suppression in plants. Quelling-defective (qde) mutants of N. crassa, in which transgene-induced gene silencing is impaired, have been isolated. Here we report the cloning of qde-1, the first cellular component of the gene-silencing mechanism to be isolated, which defines a new gene family conserved among different species including plants, animals and fungi. The qde-1 gene product is similar to an RNA-dependent RNA polymerase found in the tomato. The identification of qde-1 strongly supports models that implicate an RNA-dependent RNA polymerase in the post-transcriptional gene-silencing mechanism. The presence of qde-1 homologues in a variety of species of plants and fungi indicates that a conserved gene-silencing mechanism may exist, which could have evolved to preserve genome integrity and to protect the genome against naturally occurring transposons and viruses.

Amino Acid Sequence↗
PubMed2000

c-Abl tyrosine kinase is not essential for ataxia telangiectasia mutated functions in chromosomal maintenance.

c-Abl is activated by DNA damage in an ataxia telangiectasia mutated (ATM)-dependent manner and plays important roles in growth arrest and apoptosis induced by DNA damage. c-Abl also interacts physically and functionally with Rad51, a key molecule in homologous recombinational (HR) DNA repair. To study further the roles of c-Abl in HR DNA repair, we generated c-Abl(-/-) and ATM(-/-)/c-Abl(-/-) mutant cell lines from a chicken B lymphocyte DT40 cell line, comparing the phenotypes of these mutants to those of ATM(-/-) DT40 cells that we had created previously. We found that the time course of radiation-induced Rad51 focus formation is abnormal in ATM(-/-) DT40 cells, consistent with the observation that ATM(-/-) DT40 cells display hypersensitivity to ionizing radiation and highly elevated frequencies of both spontaneous and radiation-induced chromosomal aberrations. In contrast, c-Abl(-/-) cells did not show these ATM-related defects in their cellular response to radiation, nor did the disruption of c-Abl in ATM(-/-) DT40 cells exacerbate these ATM-related defects. However, c-Abl(-/-) DT40 cells, but not ATM(-/-) DT40 cells, were resistant to radiation-induced apoptosis, indicating an important role for c-Abl in this cellular response to ionizing radiation. These results therefore indicate that, although ATM plays an important role in genome maintenance, c-Abl is not essential for this ATM function. These findings suggest that c-Abl and ATM play important roles in the maintenance of the cell homeostasis in response to DNA damage that are, at least in part, independent.

Animals↗
PubMed2006

Haploinsufficiency in DNA polymerase beta increases cancer risk with age and alters mortality rate.

This study uses a base excision repair (BER)-deficient model, the DNA polymerase beta heterozygous mouse, to investigate the effect of BER deficiency on tumorigenicity and aging. Aged beta-pol(+/-) mice express 50% less beta-pol transcripts and protein (P < 0.05) than aged beta-pol(+/+) mice, showing maintenance of the heterozygous state over the life span of the mouse. This reduction in beta-pol expression was not associated with an increase in mutation rate but was associated with a 100% increase in the onset of hypoploidy. Aged beta-pol(+/-) mice exhibited a 6.7-fold increase in developing lymphoma (P < 0.01). Accordingly, 38% of beta-pol(+/-) mice exhibited lymphoid hyperplasia, whereas none of the beta-pol(+/+) exhibited this phenotype. beta-pol(+/-) mice were also more likely to develop adenocarcinoma (2.7-fold increase; P < 0.05) and more likely to develop multiple tumors, as 20% of the beta-pol(+/-) animals died bearing multiple tumors compared with only 5% of the beta-pol(+/+) animals (P < 0.05). In spite of accelerated tumor development, no gross effect of beta-pol heterozygosity was seen with respect to life span. However, the survival curves for the beta-pol(+/+) and beta-pol(+/-) mice are not identical. A maximum likelihood estimation analysis showed a modest but significant (P < 0.05) acceleration of the age-dependent mortality rate in beta-pol(+/-) mice. Thus, the beta-pol(+/-) mouse represents a model in which mortality rate and tumor development are accelerated and provides evidence supporting the role of genomic maintenance in both aging and carcinogenesis.

Age Factors↗
PubMed1996

There is substantial agreement among interspecies estimates of DNA repair activity.

Faithful maintenance of the genetic material is essential for cellular and organismal function. Thus the activity with which nuclear and mitochondrial DNA is repaired in somatic cells is likely to be an crucial determinant of maximal lifespan (MLS). However there has been controversy over both the actual rates of DNA repair in a variety of species, and the correlation of those rates with maximal lifespan. Five comparative studies of DNA repair have been re-analyzed with reference to an internal repair standard. Although some variance in measurements of DNA repair activity of the same species in different laboratories was observed, overall there is good agreement on the rank order of repair activity once those studies are internally calibrated. A six-fold range of relative DNA repair activity was observed, with mouse, rat and shrew lowest (0.9 to 1.0), and human and gorilla highest (4.5 to 5.3). The correlation between DNA repair activity and MLS was good, but not excellent (r2 = 0.845); a possible explanation is that active DNA repair is a necessary but not sufficient condition for long MLS. We investigated the kinetics of mitochondrial mutagenesis and tumorigenesis in mice and humans, and observed that each proceeds at a rate approximately 40-fold faster in mice than in humans. Thus one likely consequence of the deficiency of DNA repair in small rodents is an increased rate of mutagenesis and tumorigenesis. The large differences in metabolic investment in genomic maintenance in mice versus humans is a prediction of the disposable soma theory of aging, which is discussed.

Aging↗
PubMed2026

Non-coding RNAs as regulators of chromosomal instability in breast cancer.

Breast cancer is a highly heterogeneous disease characterized by extensive genomic and chromosomal instability (CIN), a hallmark that drives tumor evolution, intratumoral heterogeneity, therapeutic resistance, and poor clinical outcomes. Increasing evidence indicates that non-coding RNAs (ncRNAs) are important regulators of genome maintenance and chromosome stability. However, their specific contributions to CIN and the strength of the available evidence remain incompletely understood. This review examines the role of the major ncRNA classes, including circular RNAs, microRNAs, PIWI-interacting RNAs, small nucleolar RNAs, and long non-coding RNAs, in the regulation of CIN-related processes in breast cancer. We discuss the molecular mechanisms by which these ncRNAs regulate key pathways involved in CIN, while critically evaluating the strength of the experimental evidence supporting their functional roles. We also examine their associations with distinct breast cancer molecular subtypes and assess their potential as biomarkers and therapeutic targets, highlighting current limitations and knowledge gaps that hinder clinical translation. Collectively, the available evidence supports an emerging role for ncRNAs as regulators of CIN while underscoring the need for further mechanistic and subtype-specific studies to validate their clinical utility.

DNA repair↗
PubMed2000

Proteasome-mediated degradation of the papillomavirus E2-TA protein is regulated by phosphorylation and can modulate viral genome copy number.

The bovine papillomavirus E2 proteins regulate viral transcription, replication, and episomal genome maintenance. We have previously mapped the major phosphorylation sites of the E2 proteins to serine residues 298 and 301 and shown that mutation of serine residue 301 to alanine leads to a dramatic (10- to 20-fold) increase in viral DNA copy number. In this study we analyzed how phosphorylation regulates E2 protein function. S301 is located in a PEST sequence; these sequences are often found in proteins with a short half-life and can be regulated by phosphorylation. We show here that the E2 protein is ubiquitinated and degraded by the proteasome. Mutation of serine 301 to alanine increases the half-life of E2 from approximately 50 min to 160 min. Furthermore, the A301 E2 protein shows greatly reduced ubiquitination and degradation by the proteasome. These results suggest that the E2 protein level is regulated by phosphorylation, which in turn determines viral episomal copy number.

Alanine↗
PubMed2006

Length-dependent degradation of single-stranded 3' ends by the Werner syndrome protein (WRN): implications for spatial orientation and coordinated 3' to 5' movement of its ATPase/helicase and exonuclease domains.

BACKGROUND: The cancer-prone and accelerated aging disease Werner syndrome is caused by loss of function of the WRN gene product that possesses ATPase, 3' to 5' helicase and 3' to 5' exonuclease activities. Although WRN has been most prominently suggested to function in telomere maintenance, resolution of replication blockage and/or recombinational repair, its exact role in DNA metabolism remains unclear. WRN is the only human RecQ family member to possess both helicase and exonuclease activity, but the mechanistic relationship between these activities is unknown. In this study, model single-stranded and 3' overhang DNA substrates of varying length and structure were used to examine potential coordination between the ATPase/helicase and exonuclease activities of WRN. RESULT: Our results show that WRN can not only bind to but also catalyze the 3' to 5' degradation of single-stranded and 3' overhang DNA substrates, structures that were previously thought to be refractory to WRN exonuclease activity. The length of the single-stranded regions in these structures is a critical parameter in determining both the binding affinity and the level of exonuclease activity of WRN. Most importantly, specific nucleotide cofactors dramatically stimulate WRN exonuclease activity on these substrates, with conditions that permit ATP hydrolysis not only resulting in enhanced exonuclease activity but also altering its length dependence on these structures. Parallel experiments show that a deletion mutant containing only the WRN exonuclease domain lacks both this DNA length and nucleotide cofactor dependence, demonstrating that the interaction of the ATPase/helicase domain of WRN with the DNA substrate has a profound influence on exonuclease activity. CONCLUSION: Our results indicate that, under conditions that permit ATP hydrolysis, there is a dynamic and cooperative relationship between the distinct ATPase/helicase and exonuclease domains of WRN with regard to their orientation on DNA. Based on these results, models are proposed for the coordinated, unidirectional 3' to 5' movement of the helicase and exonuclease domains of WRN on DNA that should be informative for elucidating its function in genome maintenance.

Adenosine Triphosphatases↗
PubMed2005

Conditional inactivation of the mouse Hus1 cell cycle checkpoint gene.

The Hus1 cell cycle checkpoint protein plays a central role in genome maintenance by mediating cellular responses to DNA damage and replication stress. Targeted deletion of mouse Hus1 results in spontaneous chromosomal abnormalities and embryonic lethality. To study the physiological impact of Hus1 deficiency in adult mice, we generated a conditional Hus1 allele, Hus1(flox), in which exons two and three are flanked by loxP sites. Cre-mediated excision of the loxP-flanked region produces Hus1(Delta2,3), which is capable of encoding only 19 of 281 Hus1 amino acids. Germline homozygosity for Hus1(Delta2,3) resulted in mid-gestational embryonic lethality that was indistinguishable from that caused by an established null allele, Hus1(Delta1n). Hus1 was inactivated in adult mice using a transgenic strain in which Cre is sporadically expressed in a variety of tissues from the Hsp70-1 promoter. Conditional Hus1 knockout mice were produced at unexpectedly low frequency and, unlike control animals, demonstrated limited inactivation of the conditional allele, suggesting that Hus1-deficient cells were at a strong selective disadvantage in adult animals. However, viable conditional Hus1 knockout mice consistently showed the greatest degree of Hus1 inactivation specifically in lung and mammary gland, highlighting varying requirements for Hus1 in different tissues. The novel tools described here hold promise for elucidating how the Hus1-dependent checkpoint mechanism contributes to chromosomal stability, DNA damage responses, and tumor suppression in adult mice.

Alleles↗