Disease relevance of RECQL4

• Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome [1].
• 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 [2].
• Recently, RECQL4 was identified as the gene responsible for some cases of Rothmund-Thomson syndrome (RTS), a rare autosomal recessive genetic disorder that shows chromosomal instability, premature aging, and a high risk of mesenchymal tumors [3].
• 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 [1].
• Using a T7 phage display screen, we determined that RECQL4 interacts with poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme that promotes genomic integrity through its involvement in DNA repair and signaling pathways [4].
• RecQ4 could directly interact with xeroderma pigmentosum group A, and this interaction was stimulated by UV irradiation [5].

High impact information on RECQL4

• Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome [6].
• 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 [1].
• Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder caused by deleterious mutations in the RECQL4 gene on chromosome 8 [7].
• The RECQL4 gene structure is unusual because it contains many small introns <100 bp [7].
• It is caused by mutations in the RECQL4 gene and thus represents one of the three cancer-prone genetic diseases that are caused by mutations in a RecQ helicase-encoding gene [8].

Biological context of RECQL4

• The RECQL4 gene was localized to mouse chromosome 15D3 distal-E1 and rat chromosome 7q34 proximal [9].
• The RECQL4 gene is in a small genome of 6.5 kb and consists of 21 exons [3].
• 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 [9].
• In this study, we show the genomic organization of the RECQL4 gene, including the exon-intron boundaries, the transcription initiation sites, and the potential promoter sequences, which facilitates further mutation analysis of the RECQL4 gene and studies to elucidate the pathogenesis behind RTS [3].
• These data suggest that p53-mediated repression of RECQ4 transcription during DNA damage results from the modulation of the promoter occupancy of transcription activators and repressors [10].

Anatomical context of RECQL4

• However, in untransformed WI-38 fibroblasts, RECQL4 was found to be largely nuclear, and was present at significantly lower total levels than in transformed HeLa cells [11].
• Immunocytochemical analysis indicated that the RECQL4 protein expressed in HeLa cells is in the nucleus and appears to be localized mainly in the nucleoplasm similar to WRN helicase [3].
• RECQL4 mRNA was detected in 9 of 9 OS cell lines by Northern blotting and 26 of 26 OS tumors by RT-PCR [12].
• Successful umbilical cord blood stem cell transplantation in a patient with Rothmund-Thomson syndrome and combined immunodeficiency.The ATP-dependent DNA helicase Q4 (RECQL4) belongs to a family of conserved RECQ helicases that are felt to be important in maintaining chromosomal integrity (Kitao et al.,1998, Genomics: 54 (3): 443-452; (6)) [13].

Associations of RECQL4 with chemical compounds

• However, in a significant number of cells exposed to hydrogen peroxide or streptonigrin, RECQL4 accumulated in nucleoli [4].
• RECQL4 localization did not change after treatment with the DNA-damaging agents bleomycin, etoposide, UV irradiation and gamma irradiation, in contrast to the Bloom and Werner syndrome helicases that relocate to distinct nuclear foci after damage [4].
• We characterized two novel and one already described single-nucleotide polymorphism in the coding region of the RECQL4 gene, which were shown by the exonic splicing enhancer (ESE) score matrix to fall into high-score motifs recognized by serine/arginine-rich proteins [14].

Physical interactions of RECQL4

• The simultaneous formation of a camptothecin-dependent p53-SP1 complex indicated its occurrence outside of the RECQ4 promoter [10].
• 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 [15].

Regulatory relationships of RECQL4

• In the 5' upstream region, one Sp1 site and several AP 2 sites exist near the capping site, suggesting that the expression of RECQL4 is regulated by a housekeeping-type promoter similar to WRN [3].
• Tumor suppressor p53 represses transcription of RECQ4 helicase [10].
• The RECQL4 nucleolar localization was inhibited by pretreatment with a PARP-1 inhibitor [4].
• Our results provide the first evidence of a post-translational modification of the RECQL4 protein, and suggest that acetylation of RECQL4 by p300 regulates the trafficking of RECQL4 between the nucleus and the cytoplasm [16].

Other interactions of RECQL4

• The function of RECQL4 remains unknown, but based on the domain homology it possesses ATP-dependent DNA helicase activity such as BLM and WRN [2].
• The RECQL4 helicase gene is a member of the RECQL gene family, mutated in some Rothmund-Thomson syndrome (RTS) patients [2].
• By comparative Northern blot analysis, we show that the RECQL4 transcripts are severely down-regulated in the cells from RTS patients, similar to our previous observation for WRN transcripts in cells from Werner patients [3].
• The C-terminal portion of RECQL4 was found to be an in vitro substrate for PARP-1 [4].
• Furthermore, we demonstrate that RECQL4 foci coincide with foci formed by human Rad51 and regions of single-stranded DNA after induction of DNA double-strand breaks [17].

Analytical, diagnostic and therapeutic context of RECQL4

• Using a retrospective cohort study, we evaluated survival and mortality risk factors in our dialysis population at the Renal Unit, RTS Cauca--Nephrologic San Jose, Popaydn, Cauca, Colombia [18].

References