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)

Several eukaryotic homologs of the Escherichia coli RecQ DNA helicase have been found. These include the human BLM gene, whose mutation results in Bloom syndrome, and the human WRN gene, whose mutation leads to Werner syndrome resembling premature aging. We cloned a Drosophila melanogaster homolog of the RECQ helicase family, Dmblm (Drosophila melanogaster Bloom), which encodes a putative 1487-amino-acid protein. Phylogenetic and dot plot analyses for the RECQ family, including 10 eukaryotic and 3 prokaryotic genes, indicate Dmblm is most closely related to the Homo sapiens BLM gene, suggesting functional similarity. Also, we found that Dmblm cDNA partially rescued the sensitivity to methyl methanesulfonate of Saccharomyces cerevisiae sgs1 mutant, demonstrating the presence of a functional similarity between Dmblm and SGS1. Our analyses identify four possible subfamilies in the RECQ family: (1) the BLM subgroup (H. sapiens Bloom, D. melanogaster Dmblm, and Caenorhabditis elegans T04A11.6); (2) the yeast RECQ subgroup (S. cerevisiae SGS1 and Schizosaccharomyces pombe rqh1/rad12); (3) the RECQL/Q1 subgroup (H. sapiens RECQL/Q1 and C. elegans K02F3.1); and (4) the WRN subgroup (H. sapiens Werner and C. elegans F18C5.2). This result may indicate that metazoans hold at least three RECQ genes, each of which may have a different function, and that multiple RECQ genes diverged with the generation of multicellular organisms. We propose that invertebrates such as nematodes and insects are useful as model systems of human genetic diseases.
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PMID:Evolution of the RECQ family of helicases: A drosophila homolog, Dmblm, is similar to the human bloom syndrome gene. 1004 20

Rothmund-Thomson syndrome (RTS; also known as poikiloderma congenitale) is a rare, autosomal recessive genetic disorder characterized by abnormalities in skin and skeleton, juvenile cataracts, premature ageing and a predisposition to neoplasia. Cytogenetic studies indicate that cells from affected patients show genomic instability often associated with chromosomal rearrangements causing an acquired somatic mosaicism. The gene(s) responsible for RTS remains unknown. The genes responsible for Werner and Bloom syndromes (WRN and BLM, respectively) have been identified as homologues of Escherichia coli RecQ, which encodes a DNA helicase that unwinds double-stranded DNA into single-stranded DNAs. Other eukaryotic homologues thus far identified are human RECQL, Saccharomyces cerevisiae SGS1 and Schizosaccharomyces pombe rqh1. We recently cloned two new human helicase genes, RECQL4 at 8q24.3 and RECQL5 at 17q25, which encode members of the RecQ helicase family. Here, we report that three RTS patients carried two types of compound heterozygous mutations in RECQL4. The fact that the mutated alleles were inherited from the parents in one affected family and were not found in ethnically matched controls suggests that mutation of RECQL4 at human chromosome 8q24.3 is responsible for at least some cases of RTS.
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PMID:Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. 1031 67

Bloom syndrome (BS) is a rare genetic disorder characterized by small body size, sunsensitivity, immunodeficiency and a high predisposition to various types of cancer. BLM was identified as the causative gene for BS, and BLM protein is homologous to DNA helicase. In 1995 the causative gene for BS was identified using somatic crossover point mapping and termed BLM. BLM is a 4437 bp cDNA that encodes a 1417 amino acid peptide which is homologous to ATP-dependent DNA helicases. DNA helicases are the enzymes which catalyze the unwinding of double-stranded DNA to provide single- stranded templates for the processes of replication, repair, recombination and transcription. BLM is a member of the RecQ helicase family, consisting of human WRN, RECQL and yeast Sgs1. The BLM protein translocates into the nucleus and the distal arm of the bipartite basic residues in the C-terminus of the BLM protein is essential for targeting the nucleus. Here, we also describe relationship between the BLM gene and the cancer.
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PMID:[Bloom syndrome]. 1092 24

Five members of the RecQ helicase family, RECQL, WRN, BLM, RECQL4 and RECQL5 have been identified in humans. WRN and BLM have been demonstrated to be the responsible genes in Werner and Bloom syndromes, respectively. RECQL4 (RecQ helicase protein-like 4) was identified as a fourth member of the human RecQ helicase family bearing the helicase domain, and it was subsequently shown to be the responsible gene in Rothmund-Thomson syndrome. Here, we isolated mouse RECQL4 and determined the DNA sequence of full-length cDNA as well as the genome organization and chromosome locus. The mouse RECQL4 consists of 3651 base pairs coding 1216 amino acid residues and shares 63.4% of identical and 85.8% of homologous amino acid sequences with human RECQL4. The RECQL4 gene was localized to mouse chromosome 15D3 distal-E1 and rat chromosome 7q34 proximal. They were mapped in the region where the conserved linkage homology has been identified between the two species. Twenty-two exons dispersed over 7 kilo base pairs and all of the acceptor and donor sites for splicing of each exon conformed to the GT/AG rule. Our observations regarding mouse RECQL4 gene will contribute to functional studies on the RECQL4 products.
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PMID:Cloning, genomic structure and chromosomal localization of the gene encoding mouse DNA helicase RecQ helicase protein-like 4. 1116 12

Five members of the RecQ helicase family, RECQL, WRN, BLM, RTS and RECQL5, have been found in human and three of them (WRN, BLM and RTS) were disclosed to be the genes responsible for Werner, Bloom and Rothmund-Thomson syndromes, respectively. RECQL5 (RecQ helicase protein-like 5) was isolated as the fifth member of the family in humans through a search of homologous expressed sequence tags. The gene is expressed with at least three alternative splicing products, alpha, beta and gamma. Here, we isolated mouse RECQL5 beta and determined the DNA sequence of full-length cDNA as well as the genome organization and chromosome locus. The mouse RECQL5 beta gene consists of 2949 bp coding 982 amino acid residues. Comparison of amino acid sequence among human (Homo sapiens), mouse (Mus musculus), Drosophila melanogaster and Caenorhabditis elegans RECQL5 beta homologs revealed three portions of highly conserved regions in addition to the helicase domain. Nineteen exons are dispersed over 40 kbp in the genome and all of the acceptor and donor sites for the splicing of each exon conform to the GT/AG rule. The gene is localized to the mouse chromosome 11E2, which has a syntenic relation to human 17q25.2-q25.3 where human RECQL5 beta exists. Our genetic characterizations of the mouse RECQL5 beta gene will contribute to functional studies on the RECQL5 beta products.
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PMID:Cloning, genomic structure and chromosomal localization of the gene encoding mouse DNA helicase RECQL5beta. 1173 18

We have initiated a candidate gene approach to study variation and predisposition to cancer in the four major ethnic groups that constitute the U.S. population (African Americans, Caucasians, Hispanics, and Asians). We resequenced portions of three helicase genes (BLM, WRN, and RECQL) identifying a total of 37 noncoding single nucleotide polymorphisms (SNPs). Haplotype inference predicted 50 haplotypes in BLM, 56 in WRN, and 47 in RECQL in a sample of 600 chromosomes. Approximately 10% of the predicted haplotypes were shared among all ethnic groups. Linkage disequilibrium and recombination effects showed that each locus has taken a diverse evolutionary path. Primate DNA analysis of the same loci revealed one human haplotype per gene shared with the great apes, indicating that the observed diversity occurred since the divergence of humans from the last common ancestor. In BLM, we confirmed the presence of a founder haplotype among Ashkenazi Jews homozygous for the blm(Ash) mutation. The cosegregating haplotype was seen in all (6/6) samples of Ashkenazi descent, whereas in the general population it has a low frequency (0.02) and was not found in African Americans. In WRN, ethnic samples were studied for their haplotype content and the presence or absence of six previously described coding SNPs (cSNPs). Hispanic individuals carrying two of these cSNPs showed a 60% increase in the frequency of a common haplotype (haplotype No. 28). In the pooled sample, no association was found. Because (1) the majority of the haplotypes are population specific and (2) the patterns of linkage disequilibrium, recombination, and haplotype diversity are markedly different between gene regions, these data show the importance of either ethnically matched controls or within-family-based disease-gene association studies.
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PMID:Complex SNP-based haplotypes in three human helicases: implications for cancer association studies. 1193 47

The RECQL4 helicase gene is a member of the RECQL gene family, mutated in some Rothmund-Thomson syndrome (RTS) patients. Other members of this gene family are BLM mutated in Bloom syndrome, WRN mutated in Werner syndrome and RECQL and RECQL5. All polypeptides encoded by RECQL genes share a central region of seven helicase domains. The function of RECQL4 remains unknown, but based on the domain homology it possesses ATP-dependent DNA helicase activity such as BLM and WRN. Rothmund-Thomson, Bloom and Werner syndromes have overlapping clinical features, of which high predisposition to malignancies is the most remarkable feature. Here we report a fourth syndrome resulting in mutations in the RECQL genes. RAPADILINO syndrome is an autosomal recessive disorder characterized by short stature, radial ray defects and other malformations, as well as infantile diarrhoea, but not by a significant cancer risk. Four mutations in the RECQL4 gene were found in the Finnish patients, the most common mutation representing exon 7 in-frame deletion saving the helicase domain and showing dominant effect over other three nonsense mutations. The tissue expression of Recql4 in mouse well agrees with the tissue symptoms of RAPADILINO. The skeletal malformations in RAPADILINO and RTS patients as well as the high osteosarcoma risk in RTS propose a special role for RECQL4 in bone development.
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PMID:Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases. 1295 69

The mouse gene Recql is a member of the RecQ subfamily of DEx-H-containing DNA helicases. Five members of this family have been identified in both humans and mice, and mutations in three of these, BLM, WRN, and RECQL4, are associated with human diseases and a cellular phenotype that includes genomic instability. To date, no human disease has been associated with mutations in RECQL and no cellular phenotype has been associated with its deficiency. To gain insight into the physiological function of RECQL, we disrupted Recql in mice. RECQL-deficient mice did not exhibit any apparent phenotypic differences compared to wild-type mice. Cytogenetic analyses of embryonic fibroblasts from the RECQL-deficient mice revealed aneuploidy, spontaneous chromosomal breakage, and frequent translocation events. In addition, the RECQL-deficient cells were hypersensitive to ionizing radiation, exhibited an increased load of DNA damage, and displayed elevated spontaneous sister chromatid exchanges. These results provide evidence that RECQL has a unique cellular role in the DNA repair processes required for genomic integrity. Genetic background, functional redundancy, and perhaps other factors may protect the unstressed mouse from the types of abnormalities that might be expected from the severe chromosomal aberrations detected at the cellular level.
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PMID:RECQL, a member of the RecQ family of DNA helicases, suppresses chromosomal instability. 1715 23

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

Deregulation of DNA repair enzymes occurs in cancers and may create a susceptibility to chemotherapy. Expression levels of DNA repair enzymes have been shown to predict the responsiveness of cancers to certain chemotherapeutic agents. The RECQ helicases repair damaged DNA including damage caused by topoisomerase I inhibitors, such as irinotecan. Altered expression levels of these enzymes in colorectal cancer (CRC) may influence the response of the cancers to irinotecan. Thus, we assessed RECQ helicase (WRN, BLM, RECQL, RECQL4, and RECQL5) expression in primary CRCs, matched normal colon, and CRC cell lines. We found that BLM and RECQL4 mRNA levels are significantly increased in CRC (P = .0011 and P < .0001, respectively), whereas RECQL and RECQL5 are significantly decreased (P = .0103 and P = .0029, respectively). RECQ helicase expression patterns varied between specific molecular subtypes of CRCs. The mRNA and protein expression of the majority of the RECQ helicases was closely correlated, suggesting that altered mRNA expression is the predominant mechanism for deregulated RECQ helicase expression. Immunohistochemistry localized the RECQ helicases to the nucleus. RECQ helicase expression is altered in CRC, suggesting that RECQ helicase expression has potential to identify CRCs that are susceptible to specific chemotherapeutic agents.
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PMID:Altered RECQ Helicase Expression in Sporadic Primary Colorectal Cancers. 2390 89


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