Disease relevance of RECQL

• The RECQL4 helicase gene is a member of the RECQL gene family, mutated in some Rothmund-Thomson syndrome (RTS) patients [1].
• Cloning and characterization of RECQL, a potential human homologue of the Escherichia coli DNA helicase RecQ [2].
• The addition of these genes increases the total to five helicase genes in the human RecQ family, which includes helicases involved in Bloom and Werner syndromes, the genetic diseases manifesting the distinctive but overlapping clinical phenotypes of immunodeficiency, premature aging, and an enhanced risk of cancer [3].
• Werner's syndrome (WS) is a rare autosomal recessive disorder that arises as a consequence of mutations in a gene coding for a protein that is a member of RecQ family of DNA helicases, WRN [4].
• Characterization and mutational analysis of the RecQ core of the bloom syndrome protein [5].

High impact information on RECQL

• To better understand the cellular role of the RecQ-like DNA helicases, sgs1 mutations were analyzed for their effect on genome rearrangements [6].
• We recently cloned two new human helicase genes, RECQL4 at 8q24.3 and RECQL5 at 17q25, which encode members of the RecQ helicase family [7].
• In this novel mapping method, cells were used from persons with BS that had undergone intragenic recombination within BLM. cDNA analysis of the candidate gene identified a 4437 bp cDNA that encodes a 1417 amino acid peptide with homology to the RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases [8].
• In animals, genes that are homologous to RecQ protein, such as the human genes for Bloom's syndrome and Werner's syndrome, may also function in PTGS [9].
• Posttranscriptional gene silencing in Neurospora by a RecQ DNA helicase [9].

Chemical compound and disease context of RECQL

• To define the physical basis of RecQ enzyme function, we have determined a 1.8 A resolution crystal structure of the catalytic core of Escherichia coli RecQ in its unbound form and a 2.5 A resolution structure of the core bound to the ATP analog ATPgammaS [10].
• Several RecQ family of helicases contain a putative zinc finger motif of the C4 type at the C terminus that has been identified in the crystalline structure of RecQ helicase from Escherichia coli [11].
• One example is the RecQ helicase family, named after the RecQ protein of Escherichia coli, which was identified during a search for mutants sensitive to thymine starvation [12].

Biological context of RECQL

• Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases [1].
• Haplotype inference predicted 50 haplotypes in BLM, 56 in WRN, and 47 in RECQL in a sample of 600 chromosomes [13].
• We resequenced portions of three helicase genes (BLM, WRN, and RECQL) identifying a total of 37 noncoding single nucleotide polymorphisms (SNPs) [13].
• The RECQL cDNA contains a protein coding region of 1977 base pairs, and encodes a 659-amino-acid polypeptide with a predicted M(r) 72,000 [2].
• RECQL was localized to human chromosome 12 by analysis of human-rodent somatic cell hybrid DNA; fine mapping of RECQL by fluorescence in situ hybridization revealed its chromosomal location to be 12p11-p12 [14].

Anatomical context of RECQL

• These antibodies demonstrated that RECQL is located predominantly in the nucleus of human fibroblasts [2].
• A potential human DNA helicase, RECQL, was partially purified from HeLa cells, and a cDNA encoding this protein was subsequently cloned from a HeLa library [2].
• Expression of the RECQL cDNA in reticulocyte lysates and in transiently transfected cells confirms the M(r) 72,000 of the protein; this protein reacted with antibodies raised against synthetic peptides comprising both the predicted amino- and carboxyl-terminal sequences [2].
• We also roughly determined the number of copies per cell for the five RecQ helicase in B cells [15].
• In addition, levels of the different RecQ helicases are modulated in different ways during the cell cycle of actively proliferating fibroblasts and umbilical endothelial cells [15].

Associations of RECQL with chemical compounds

• RecQ helicase BLM-deficient cells are characteristically hypersensitive to 4-nitroquinoline-1-oxide (4NQO) [16].
• Some were novel candidates, while others are involved in well-characterized mechanisms that could be relevant to cisplatin resistance, such as RECQL for DNA repair and MAP2K6 in the MAP pathway; all the genes were further validated by Real-time PCR [17].
• In budding and fission yeasts, loss of RecQ helicase function confers sensitivity to inhibitors of DNA replication, such as hydroxyurea (HU), by failure to execute normal cell cycle progression following recovery from such an S-phase arrest [18].
• In addition, mutation of Rad60 Ser(32) and Ser(34) to alanine is lethal in cells deleted for the RecQ DNA helicase Rqh1 [19].
• Steady-state fluorescence anisotropy measurements of fluorescein-labeled oligonucleotides revealed that RecQ helicase bound to DNA with an apparent binding stoichiometry of 1 protein monomer/10 nucleotides [20].

Physical interactions of RECQL

• The mapping analysis of protein interaction sites in WRN for most of its binding partners have revealed a common site of protein-protein interaction in the RecQ conserved (RQC) region of WRN [21].
• Further work is needed to define the specific and shared functions of RECQL4 in relation to other RecQ helicases and to connect RECQL4 diseases to other genomic instability syndromes with birth defects and cancer predisposition [22].

Other interactions of RECQL

• Functional relation among RecQ family helicases RecQL1, RecQL5, and BLM in cell growth and sister chromatid exchange formation [23].
• Currently, WRN is the only member of the widely distributed RecQ DNA helicase family with documented exonuclease activity [24].
• 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 [25].
• Catenated DNA is the predominant product under conditions of molecular crowding; however, we also discovered that RecQ helicase and single-stranded DNA-binding protein greatly stimulated the intramolecular strand passage ("supercoiling") activity of Topo III, as revealed by changes in the linking number of uncatenated DNA [26].
• Substrate-specific DNA binding activity was detected in three domains, one N-terminal and two different C-terminal WRN fragments (RecQ conserved domain and helicase RNase D conserved domain-containing domains) [27].

Analytical, diagnostic and therapeutic context of RECQL

• Molecular cloning of a splicing variant of human RECQL helicase [28].
• MATERIALS AND METHODS: The sequence alignment was performed for RecQ DNA helicases and Rep and PcrA helicases [29].
• Titration data suggest that an intermediate of the RecQ helicase unwinding process, perhaps a RecQ helicase-DNA fork, is the target for Topo III action [26].
• Here we directly assessed the structure of the catenated DNA species formed by RecQ helicase and Topo III using atomic force microscopy [26].
• When we examined colocalization and co-immunoprecipitation of p53pSer15 and the RecQ helicase BLM with recombination surveillance and proapoptotic functions, we observed colocalization within a fraction of approximately 70% of the BLM foci and stable physical interactions until 6 h after replication arrest [30].

References