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 WRN DNA helicase is a member of the DExH-containing DNA helicase superfamily that includes XPB, XPD, and BLM. Mutations in WRN are found in patients with the premature aging and cancer susceptibility syndrome known as Werner syndrome (WS). p53 binds to the WRN protein in vivo and in vitro through its carboxyl terminus. WS fibroblasts have an attenuated p53- mediated apoptotic response, and this deficiency can be rescued by expression of wild-type WRN. These data support the hypothesis that p53 can induce apoptosis through the modulation of specific DExH-containing DNA helicases and may have implications for the cancer predisposition observed in WS patients.
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PMID:p53-mediated apoptosis is attenuated in Werner syndrome cells. 1036 53

DNA helicases are a highly conserved group of enzymes that unwind DNA. They function in all processes in which access to single-stranded DNA is required, including DNA replication, DNA repair and recombination, and transcription of RNA. Defects in helicases functioning in one or more of these processes can result in characteristic human genetic disorders in which genomic instability and predisposition to cancer are common features. So far, different helicase genes have been found mutated in six such disorders. Mutations in XPB and XPD can result in xeroderma pigmentosum, Cockayne syndrome, or trichothiodystrophy. Mutations in the RecQ-like genes BLM, WRN, and RECQL4 can result in Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome, respectively. Because XPB and XPD function in both nucleotide excision repair and transcription initiation, the cellular phenotypes associated with a deficiency of each one of them include failure to repair mutagenic DNA lesions and defects in the recovery of RNA transcription after UV irradiation. The functions of the RecQ-like genes are unknown; however, a growing body of evidence points to a function in restarting DNA replication after the replication fork has become stalled. The genomic instability associated with mutations in the RecQ-like genes includes spontaneous chromosome instability and elevated mutation rates. Mouse models for nearly all of these entities have been developed, and these should help explain the widely different clinical features that are associated with helicase mutations.
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PMID:DNA helicases, genomic instability, and human genetic disease. 1170 36

Mutations in several DExH-containing DNA helicases, including XPD, XPB, WRN, and BLM, are associated with rare familial cancer syndromes characterized by genomic instability and cancer susceptibility. Known cellular activities of these helicases include DNA replication, repair, recombination, and/or transcription. The p53 tumor suppressor is a regulator of cellular responses to stress, and is biochemically involved in the induction of cell-cycle arrest, apoptosis and DNA repair, all of which contribute to maintenance of genomic integrity. Physical and functional interactions of p53 with DExH-containing DNA helicases have been described. We propose that such interactions could be compromised in inherited disorders and contribute to their cancer susceptibility. In particular, the role of DNA helicases in p53-mediated apoptotic pathways is reviewed.
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PMID:p53-mediated apoptosis and genomic instability diseases. 1176 63

Two systems are essential in humans for genome integrity, DNA repair and apoptosis. Cells that are defective in DNA repair tend to accumulate excess DNA damage. Cells defective in apoptosis tend to survive with excess DNA damage and thus allow DNA replication past DNA damages, causing mutations leading to carcinogenesis. It has recently become apparent that key proteins which contribute to cellular survival by acting in DNA repair become executioners in the face of excess DNA damage. Five major DNA repair pathways are homologous recombinational repair (HRR), non-homologous end joining (NHEJ), nucleotide excision repair (NER), base excision repair (BER) and mismatch repair (MMR). In each of these DNA repair pathways, key proteins occur with dual functions in DNA damage sensing/repair and apoptosis. Proteins with these dual roles occur in: (1) HRR (BRCA1, ATM, ATR, WRN, BLM, Tip60 and p53); (2) NHEJ (the catalytic subunit of DNA-PK); (3) NER (XPB, XPD, p53 and p33(ING1b)); (4) BER (Ref-1/Ape, poly(ADP-ribose) polymerase-1 (PARP-1) and p53); (5) MMR (MSH2, MSH6, MLH1 and PMS2). For a number of these dual-role proteins, germ line mutations causing them to be defective also predispose individuals to cancer. Such proteins include BRCA1, ATM, WRN, BLM, p53, XPB, XPD, MSH2, MSH6, MLH1 and PMS2.
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PMID:DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. 1205 32

A subset of DNA helicases, the RecQ family, has been found to be associated with the p53-mediated apoptotic pathway and is involved in maintaining genomic integrity. This family contains the BLM and WRN helicases, in which germline mutations are responsible for Bloom and Werner syndromes, respectively. TFIIH DNA helicases, XPB and XPD, are also components in this apoptotic pathway. We hypothesized that there may be some redundancy between helicases in their ability to complement the attenuated p53-mediated apoptotic levels seen in cells from individuals with diseases associated with these defective helicase genes. The attenuated apoptotic phenotype in Bloom syndrome cells was rescued not only by ectopic expression of BLM, but also by WRN or XPB, both 3' --> 5' helicases, but not expression of the 5' --> 3' helicase XPD. Overexpression of Sgs1, a WRN/BLM yeast homolog, corrected the reduction in BS cells only, which is consistent with Sgs1 being evolutionarily most homologous to BLM. A restoration of apoptotic levels in cells from WS, XPB or XPD patients was attained only by overexpression of the specific helicase. Our data suggest a limited redundancy in the pathways of these RecQ helicases in p53-induced apoptosis.
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PMID:Redundancy of DNA helicases in p53-mediated apoptosis. 1628 11

DNA helicases are molecular motors that catalyse the unwinding of energetically unstable structures into single strands and have therefore an essential role in nearly all metabolism transactions. Defects in helicase function can result in human syndromes in which predisposition to cancer and genomic instability are common features. So far different helicase genes have been found associated in 8 such disorders. RecQ helicases are a family of conserved enzymes required for maintaining the genome integrity that function as suppressors of inappropriate recombination. Mutations in RecQ4, BLM and WRN give rise to various disorders: Bloom syndrome, Rothmund-Thomson syndrome, and Werner syndrome characterized by genomic instability and increased cancer susceptibility. The DNA helicase BRIP1/BACH1 is involved in double-strand break repair and is defective in Fanconi anemia complementation group J. Mutations in XPD and XPB genes can result in xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, three genetic disorders with different clinical features but with association of transcription and NER defects. This review summarizes our current knowledge on the diverse biological functions of these helicases and the molecular basis of the associated diseases.
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PMID:[DNA helicases and human diseases]. 1715 31

Helicases have important roles in nucleic acid metabolism, and their prominence is marked by the discovery of genetic disorders arising from disease-causing mutations. Missense mutations can yield unique insight to molecular functions and basis for disease pathology. XPB or XPD missense mutations lead to Xeroderma pigmentosum, Cockayne's syndrome, Trichothiodystrophy, or COFS syndrome, suggesting that DNA repair and transcription defects are responsible for clinical heterogeneity. Complex phenotypes are also observed for RECQL4 helicase mutations responsible for Rothmund-Thomson syndrome, Baller-Gerold syndrome, or RAPADILINO. Bloom's syndrome causing missense mutations are found in the conserved helicase and RecQ C-terminal domain of BLM that interfere with helicase function. Although rare, patient-derived missense mutations in the exonuclease or helicase domain of Werner syndrome protein exist. Characterization of WRN separation-of-function mutants may provide insight to catalytic requirements for suppression of phenotypes associated with the premature aging disorder. Characterized FANCJ missense mutations associated with breast cancer or Fanconi anemia interfere with FANCJ helicase activity required for DNA repair and the replication stress response. For example, a FA patient-derived mutation in the FANCJ Iron-Sulfur domain was shown to uncouple its ATPase and translocase activity from DNA unwinding. Mutations in DDX11 (ChlR1) are responsible for Warsaw Breakage syndrome, a recently discovered autosomal recessive cohesinopathy. Ongoing and future studies will address clinically relevant helicase mutations and polymorphisms, including those that interfere with key protein interactions or exert dominant negative phenotypes (e.g., certain mutant alleles of Twinkle mitochondrial DNA helicase). Chemical rescue may be an approach to restore helicase activity in loss-of-function helicase disorders. Genetic and biochemical analyses of disease-causing missense mutations in human helicase disorders have led to new insights to the molecular defects underlying aberrant cellular and clinical phenotypes.
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PMID:Disease-causing missense mutations in human DNA helicase disorders. 2327 57