Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D03229 (BLM)
1,348 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the function of the interaction between WRN (Werner syndrome gene product) and Ku70 and between WRN and DNA-PKcs, which are components of the DNA-PKcs/Ku70/Ku80 complex, by generating KU70(-/-)/WRN(-/-) and DNA-PKcs(-/-/-)/WRN(-/-) double-gene knockout chicken DT40 cells. When treated with camptothecin (CPT), an inhibitor of DNA topoisomerase I, WRN(-/-) cells showed higher sensitivity than wild-type cells, whereas KU70(-/-) and DNA-PKcs(-/-/-) cells showed hyper-resistance. Disruption of KU70 or DNA-PKcs suppressed the sensitivity of WRN(-/-) cells to CPT, rendering them as resistant to CPT treatment as KU70(-/-) and DNA-PKcs(-/-/-) cells. On the other hand, CPT sensitivity of BLM(-/-) cells, which are defective in a RecQ helicase similar to WRN, was enhanced by deletion of KU70. The implications for the function of WRN in the non-homologous end-joining pathway of DNA repair involving Ku70 and DNA-PKcs, which may be the cause of lethality in the presence of CPT, will be discussed.
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PMID:WRN counteracts the NHEJ pathway upon camptothecin exposure. 1730 82

The RecQ family of DNA helicases is highly conserved throughout evolution and plays an important role in the maintenance of genomic stability in all organisms. Mutations in three of the five known family members in humans, BLM, WRN and RECQL4, give rise to disorders that are characterized by predisposition to cancer and premature aging, emphasizing the importance of studying the RecQ proteins and their cellular activities. Interestingly, three autosomal recessive disorders have been associated with mutations in the RECQL4 gene: Rothmund-Thomson, RAPADILINO, and Baller-Gerold syndromes, thus making RECQL4 unique within the RecQ family of DNA helicases. To date, however, the molecular function of RECQL4 and the possible cellular pathways in which it is involved remain poorly understood. Here, we present an overview of recent findings in connection with RECQL4 and try to highlight different directions the field could head, helping to clarify the role of RECQL4 in preventing tumorigenesis and maintenance of genome integrity in humans.
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PMID:The molecular role of the Rothmund-Thomson-, RAPADILINO- and Baller-Gerold-gene product, RECQL4: recent progress. 1736 46

In the cell, the unwinding of double-stranded polynucleotides is catalyzed by helicases that are present in all kingdoms of life from virus to man. Viruses, like all other organisms, synthesize their DNA or RNA genomes in a template-dependent manner. In addition to DNA or RNA polymerases, a helicase is therefore required to displace the single-stranded genome after replication, thus leading to the formation of progeny viral particles. In drug design against viral helicases, a number of viral helicase inhibitors have been developed and used in clinical studies. In humans, DNA helicases play essential roles in facilitating cellular DNA metabolisms including genome replication, DNA repair, recombination, transcription as well as telomere maintenance. The care-taker roles of helicases suggest that they might be suitable for targeting to prevent cell proliferation during carcinogenesis. Identifying helicase specific-inhibitors may lead to the development of drugs in the treatment of human cancers. In addition, some helicases such as BLM and WRN interact physically and functionally with telomerases and are involved in telomere maintenance. Hence, an antitumor therapy designed to interfere with both helicases and telomerases may be much more effective than the helicase or telomerase inhibitors alone. This review addresses these topics and discusses the design of antiviral and antitumoral agents based on the knowledge of structures and functions of helicases.
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PMID:Helicases as antiviral and anticancer drug targets. 1743 Jan 43

DNA alterations of every type are associated with the incidence of carcinogenesis, often on the genomic scale. Although homologous recombination (HR) is an important pathway of DNA repair, evidence is accumulating that deleterious genomic rearrangements can result from HR. It therefore follows that HR events may play a causative role in carcinogenesis. HR is elevated in response to carcinogens. HR may also be increased or decreased when its upstream regulation is perturbed or components of the HR machinery itself are not fully functional. This chapter summarizes research findings that demonstrate an association between HR and carcinogenesis. Increased or decreased frequencies of HR have been found in cancer cells and cancer-prone hereditary human disorders characterized by mutations in genes playing a role in HR, such as ATM, Tp53, BRCA, BLM, and WRN genes. Another evidence linking perturbations in HR and carcinogenesis is provided by studies showing that exposure to carcinogens results in an increased frequency of HR resulting in DNA deletions in yeast, human cells, or mice.
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PMID:Involvement of homologous recombination in carcinogenesis. 1745 46

The recQ gene of Escherichia coli is the founding member of the RecQ family of helicases. Like E. coli, lower eukaryotic species also possess single RecQ proteins, such as Sgs1 and Rqh1 in budding and fission yeast, respectively. However, there are five RecQ helicases in human as well as in chicken cells. Three of the human RecQ helicases are encoded by BLM, WRN and RECQL4 genes, defects of which give rise to the cancer predisposition disorders known as Bloom syndrome (BS), Werner syndrome (WS) and Rothmund-Thomson syndrome (RTS), respectively. The other two, RECQL1 and RECQL5, have not been associated with human diseases. Characterization of RecQ family proteins in unicellular organisms has revealed that their defects confer genomic instability and impairment of homologous recombination. Although systematic genetic analysis of human BS, WS, and RTS cells must be useful to understand their functions, such approach is hampered by the difficulty of making cell lines with double gene disruptions. In this context, the chicken DT40 cell line is an ideal experimental tool for sophisticated approaches that illuminate the functions of vertebrate RecQ helicases. Here, we briefly review general features of RecQ helicases and describe their functions as revealed by analysis of DT40 cells.
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PMID:Function of recQ family helicase in genome stability. 1762

BLM, the protein mutated in Bloom's syndrome, possesses a helicase activity that can dissociate DNA structures, including the Holliday junction, expected to arise during homologous recombination. BLM is stably associated with topoisomerase IIIalpha (Topo IIIalpha) and the BLAP75 protein. The BLM-Topo IIIalpha-BLAP75 (BTB) complex can efficiently resolve a DNA substrate that harbors two Holliday junctions (the double Holliday junction) in a non-crossover manner. Here we show that the Holliday junction unwinding activity of BLM is greatly enhanced as a result of its association with Topo IIIalpha and BLAP75. Enhancement of this BLM activity requires both Topo IIIalpha and BLAP75. Importantly, Topo IIIalpha cannot be substituted by Escherichia coli Top3, and the Holliday junction unwinding activity of BLM-related helicases WRN and RecQ is likewise impervious to Topo IIIalpha and BLAP75. However, the topoisomerase activity of Topo IIIalpha is dispensable for the enhancement of the DNA unwinding reaction. We have also ascertained the requirement for the BLM ATPase activity in double Holliday junction dissolution and DNA unwinding by constructing, purifying, and characterizing specific mutant variants that lack this activity. These results provide valuable information concerning how the functional integrity of the BTB complex is governed by specific protein-protein interactions among the components of this complex and the enzymatic activities of BLM and Topo IIIalpha.
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PMID:Holliday junction processing activity of the BLM-Topo IIIalpha-BLAP75 complex. 1772 55

The SUV3 gene is present in all eukaryotes and encodes an RNA/DNA helicase which operates both in mitochondria and cell nuclei. To assess its function in mammals we generated a mouse mutant strain in which the 3' part of the SUV3 gene is disrupted. The mutated allele is a hypomorph transmitted from one generation to another at a frequency about 35% lower than expected while mice homozygous for the mutation die in utero before midgestation. Using ELISA binding assays we show that human SUV3 protein interacts with human WRN and BLM helicases. The binding to BLM protein was 10-fold stronger (with a K(d) of 0.5nM) than to WRN protein (K(d) of 5nM). Silencing of the SUV3 gene in the human cell line HeLa resulted in elevation of homologous recombination as measured by the frequency of sister chromatid exchange during mitotic cell division. These results indicate that the SUV3 protein is required in mammalian development and in somatic cells participates in genome maintenance through interaction with other genome fidelity housekeepers.
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PMID:Interaction of human SUV3 RNA/DNA helicase with BLM helicase; loss of the SUV3 gene results in mouse embryonic lethality. 1796 33

Mutations in genes for WRN and BLM RecQ family helicases cause cancer prone syndromes. Werner syndrome, resulting from WRN mutation, is a segmental progeria. Endogenous WRN and BLM proteins localize in nucleoli and in nuclear PML bodies defined by isoforms of the PML protein, which is a key regulator of cellular senescence. We further characterized WRN and BLM localization using labeling with monomeric red fluorescence protein (mRFP). When ectopically expressed, mRFP-WRN (or untagged WRN) forms nuclear bodies, which are donut-shaped in some cells. We identified PML isoforms associating with the nuclear bodies. Interestingly, mRFP-WRN relocalizes from nucleoli to the nucleoplasm, frequently showing conspicuous nucleolar exclusion as well as a decrease in frequency of mRFP-WRN nuclear bodies in response to overexpression of wild-type and deacetylase mutant (H363Y) SIRT1 proteins. Similar nucleolar relocalization in response to wild-type SIRT1 was detected for mRFP-labeled BLM. Moreover, increased SIRT1 expression was associated with the downregulation of endogenous WRN and a decreased frequency of cells with BRCA1 foci. Our data indicate for the first time that SIRT1 protein may be functionally associated with WRN and BLM helicases and that some major SIRT1 functions may not require its deacetylase activity.
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PMID:Expression and localization of Werner syndrome protein is modulated by SIRT1 and PML. 1799 22

Members of the RecQ helicase family play critical roles in genome maintenance. There are five RecQ homologs in mammals, and defects in three of these (BLM, WRN, and RECQL4) give rise to cancer predisposition syndromes in humans. RECQL and RECQL5 have not been associated with a human disease. Here we show that deletion of Recql5 in mice results in cancer susceptibility. Recql5-deficient cells exhibit elevated frequencies of spontaneous DNA double-strand breaks and homologous recombination (HR) as scored using a reporter that harbors a direct repeat, and are prone to gross chromosomal rearrangements in response to replication stress. To understand how RECQL5 regulates HR, we use purified proteins to demonstrate that human RECQL5 binds the Rad51 recombinase and inhibits Rad51-mediated D-loop formation. By biochemical means and electron microscopy, we show that RECQL5 displaces Rad51 from single-stranded DNA (ssDNA) in a reaction that requires ATP hydrolysis and RPA. Together, our results identify RECQL5 as an important tumor suppressor that may act by preventing inappropriate HR events via Rad51 presynaptic filament disruption.
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PMID:RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments. 1805 18

Werner and Bloom syndromes are human diseases characterized by premature age-related defects including elevated cancer incidence. Using a novel Saccharomyces cerevisiae model system for aging and cancer, we show that cells lacking the RecQ helicase SGS1 (WRN and BLM homologue) undergo premature age-related changes, including reduced life span under stress and calorie restriction (CR), G1 arrest defects, dedifferentiation, elevated recombination errors, and age-dependent increase in DNA mutations. Lack of SGS1 results in a 110-fold increase in gross chromosomal rearrangement frequency during aging of nondividing cells compared with that generated during the initial population expansion. This underscores the central role of aging in genomic instability. The deletion of SCH9 (homologous to AKT and S6K), but not CR, protects against the age-dependent defects in sgs1Delta by inhibiting error-prone recombination and preventing DNA damage and dedifferentiation. The conserved function of Akt/S6k homologues in lifespan regulation raises the possibility that modulation of the IGF-I-Akt-56K pathway can protect against premature aging syndromes in mammals.
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PMID:Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system. 1819 2


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