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)

The RecQ-related family of DNA helicases is required for the maintenance of genomic stability in organisms ranging from bacteria to humans. In humans, mutation of three RecQ-related helicases, BLM, WRN and RecQL4, cause the cancer-prone and premature ageing diseases of Bloom syndrome, Werner's syndrome and Rothmund-Thompson syndrome, respectively. In the fission yeast Schizosaccharomyces pombe, disruption of the rqh1(+) gene, which encodes the single Sz. pombe RecQ-related helicase, causes cells to display reduced viability and elevated levels of chromosome loss. After S-phase arrest or DNA damage, cells lacking rqh1(+) function display elevated levels of homologous recombination and defective chromosome segregation. Here we show that, like other RecQ family members, the Rqh1p protein displays 3' to 5' DNA helicase activity. Interestingly, however, unlike other RecQ family members, the helicase activity of Rqh1p is only partially required for its function in recovery from S-phase arrest or DNA damage. We also report that high cellular levels of Rqh1p result in lethal chromosome segregation defects, while more moderate levels of Rqh1p cause significantly elevated rates of chromosome loss. This suggests that careful regulation of RecQ-like protein levels in eukaryotic cells is vital for maintaining genome stability.
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PMID:Helicase activity is only partially required for Schizosaccharomyces pombe Rqh1p function. 1247 86

RecQ family DNA helicases are defined as proteins sharing a homologous region with Escherichia coli RecQ and are basically regarded as enzymes involved in recombination. Humans have five RecQ family members, and deficiencies in three of them, BLM, WRN, and RTS, cause Bloom's, Werner's, and Rothmund-Thomson syndromes, respectively, each characterized by genomic instability and cancer predisposition. In this context, an important function of the RecQ homologs appears to be the unwinding of intermediates of recombination, thereby preventing its uncontrolled execution. As a consequence, their deficiencies give rise to elevated levels of recombination (the hyper-recombination phenotype), which result in chromosomal aberrations including loss of heterozygosity, a common chromosomal change associated with malignancies. Thus, those helicases qualify as caretaker-type tumor suppressor proteins. In addition, BLM and WRN deficiencies have been shown to attenuate p53-mediated apoptosis, suggesting that they also belong to the gatekeeper class of tumor suppressor proteins.
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PMID:RecQ family helicases: roles as tumor suppressor proteins. 1248 16

RecQ5 is one of five RecQ helicase homologs identified in humans. Three of the human RecQ homologs (BLM, WRN and RTS) have been linked to autosomal recessive human genetic disorders (Bloom syndrome, Werner syndrome and Rothmund-Thomson syndrome, respectively) that display increased genomic instability and cause elevated levels of cancers in addition to other symptoms. To understand the role of RecQ helicases in maintaining genomic stability, the WRN, BLM and Escherichia coli RecQ helicases have been characterized in terms of their DNA substrate specificity. However, little is known about other members of the RecQ family. Here we show that Drosophila RECQ5 helicase is a structure-specific DNA helicase like the other RecQ helicases biochemically characterized so far, although the substrate specificity is not identical to that of WRN and BLM helicases. Drosophila RECQ5 helicase is capable of unwinding 3' Flap, three-way junction, fork and three-strand junction substrates at lower protein concentrations compared to 5' Flap, 12 nt bubble and synthetic Holliday junction structures, which can be unwound efficiently by WRN and BLM.
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PMID:Analysis of helicase activity and substrate specificity of Drosophila RECQ5. 1259 64

The members of the RecQ family of DNA helicases play conserved roles in the preservation of genome integrity. RecQ helicases are implicated in Bloom and Werner syndromes, which are associated with genomic instability and predisposition to cancers. The human BLM and WRN helicases are required for normal S phase progression. In contrast, Saccharomyces cerevisiae cells deleted for SGS1 grow with wild-type kinetics. To investigate the role of Sgs1p in DNA replication, we have monitored S phase progression in sgs1Delta cells. Unexpectedly, we find that these cells progress faster through S phase than their wild-type counterparts. Using bromodeoxyuridine incorporation and DNA combing, we show that replication forks are moving more rapidly in the absence of the Sgs1 helicase. However, completion of DNA replication is strongly retarded at the rDNA array of sgs1Delta cells, presumably because of their inability to prevent recombination at stalled forks, which are very abundant at this locus. These data suggest that Sgs1p is not required for processive DNA synthesis but prevents genomic instability by coordinating replication and recombination events during S phase.
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PMID:The yeast Sgs1 helicase is differentially required for genomic and ribosomal DNA replication. 1268 26

Human RECQL1 and RECQL5 belong to the RecQ family that includes Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome causative genes. Cells derived from individuals suffering from these syndromes show significant levels of genomic instability. However, neither RECQL1 nor RECQL5 has been related to a disease, and nothing is known about the functions of RecQL1 and RecQL5. We generated here RECQL1(-/-), RECQL5(-/-), RECQL1(-/-)/RECQL5(-/-), RECQL1(-/-)/BLM(-/-), and RECQL5(-/-)/BLM(-/-) cells from chicken B-lymphocyte line DT40 cells. Although BLM(-/-) DT40 cells showed a slow-growth phenotype, a higher sensitivity to methyl methanesulfonate than the wild type, and an approximately 10-fold increase in the frequency of sister chromatid exchange (SCE) compared to wild-type cells, RECQL1(-/-), RECQL5(-/-), and RECQL1(-/-)/RECQL5(-/-) cells showed no significant difference from the wild-type cells in growth, sensitivity to DNA-damaging agents, and the frequency of SCE. However, both RECQL1(-/-)/BLM(-/-) and RECQL5(-/-)/BLM(-/-) cells grew more slowly than BLM(-/-) cells because of the increase in the population of dead cells, indicating that RecQL1 and RecQL5 are somehow involved in cell viability under the BLM function-impaired condition. Surprisingly, RECQL5(-/-)/BLM(-/-) cells showed a higher frequency of SCE than BLM(-/-) cells, indicating that RecQL5 suppresses SCE under the BLM function-impaired condition.
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PMID:Functional relation among RecQ family helicases RecQL1, RecQL5, and BLM in cell growth and sister chromatid exchange formation. 1272 11

The RecQ helicases represent a subfamily of DNA helicases that are highly conserved in evolution. Loss of RecQ helicase function leads to a breakdown in the maintenance of genome integrity, in particular hyper-recombination. Germ-line defects in three of the five known human RecQ helicases give rise to defined genetic disorders associated with cancer predisposition and/or premature aging. These are Bloom's syndrome, Werner's syndrome and Rothmund-Thomson syndrome, which are caused by defects in the genes BLM, WRN and RECQ4 respectively. Here we review the properties of RecQ helicases in organisms from bacteria to humans, with an emphasis on the biochemical functions of these enzymes and the range of protein partners that they operate with. We will discuss models in which RecQ helicases are required to protect against replication fork demise, either through prevention of fork breakdown or restoration of productive DNA synthesis.
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PMID:RecQ helicases: suppressors of tumorigenesis and premature aging. 1280 43

The Arabidopsis genome contains seven genes that belong to the RecQ family of ATP-dependent DNA helicases. RecQ members in Saccharomyces cerevisiae (SGS1) and man (WRN, BLM and RecQL4) are involved in DNA recombination, repair and genome stability maintenance, but little is known about the function of their plant counterparts. The Arabidopsis thaliana RecQsim gene is remarkably different from the other RecQ-like genes due to an insertion in its helicase domain. We isolated the AtRecQsim orthologues from rice and rape and established the presence of a similar insertion in their helicase domain, which suggests a plant specific function for the insert. The expression pattern of the AtRecQsim gene was compared with the other Arabidopsis RecQ-like members in different tissues and in response to stress. The transcripts of the AtRecQsim gene were found in all plant organs and its accumulation was higher in roots and seedlings, as compared to the other AtRecQ-like members. In contrast to most AtRecQ-like genes, the examined environmental cues did not have a detectable effect on the accumulation of the AtRecQsim transcripts. The budding yeast sgs1 mutant, which is known to be hypersensitive to the DNA-damaging drug MMS, was transformed with the AtRecQsim cDNA. The AtRecQsim gene suppressed the MMS hypersensitivity phenotype of the sgs1 cells. We propose that the Arabidopsis RecQsim gene, despite its unusual structure, exhibits an evolutionary conserved function.
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PMID:Arabidopsis RecQsim, a plant-specific member of the RecQ helicase family, can suppress the MMS hypersensitivity of the yeast sgs1 mutant. 1285 35

The human aging diseases Werner and Bloom syndromes are a result of mutation of the WRN and BLM genes, respectively. The SGS1 gene of Saccharomyces cerevisiae is homologous to the human WRN and BLM genes of the RecQ DNA helicase family. Deletion of SGS1 results in accelerated yeast aging and a reduction in life span as well as cell cycle arrest. We demonstrate that SGS1 deletion, DNA damage, and stress show similar transcriptional responses in yeast. Our comparative analysis of the genome-wide expression response of SGS1 deletion, stress and DNA damage indicates parallel transcriptional responses to cellular insult and aging in yeast.
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PMID:DNA damage and stress transcripts in Saccharomyces cerevisiae mutant sgs1. 1287 47

Werner syndrome (WS) predisposes patients to cancer and premature aging, owing to mutations in WRN. The WRN protein is a RECQ-like helicase and is thought to participate in DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) or homologous recombination (HR). It has been previously shown that non-homologous DNA ends develop extensive deletions during repair in WS cells, and that this WS phenotype was complemented by wild-type (wt) WRN. WRN possesses both 3' --> 5' exonuclease and 3' --> 5' helicase activities. To determine the relative contributions of each of these distinct enzymatic activities to DSB repair, we examined NHEJ and HR in WS cells (WRN-/-) complemented with either wtWRN, exonuclease-defective WRN (E-), helicase-defective WRN (H-) or exonuclease/helicase-defective WRN (E-H-). The single E-and H- mutants each partially complemented the NHEJ abnormality of WRN-/- cells. Strikingly, the E-H- double mutant complemented the WS deficiency nearly as efficiently as did wtWRN. Similarly, the double mutant complemented the moderate HR deficiency of WS cells nearly as well as did wtWRN, whereas the E- and H- single mutants increased HR to levels higher than those restored by either E-H- or wtWRN. These results suggest that balanced exonuclease and helicase activities of WRN are required for optimal HR. Moreover, WRN appears to play a structural role, independent of its enzymatic activities, in optimizing HR and efficient NHEJ repair. Another human RECQ helicase, BLM, suppressed HR but had little or no effect on NHEJ, suggesting that mammalian RECQ helicases have distinct functions that can finely regulate recombination events.
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PMID:WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair. 1293 12

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


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