RECQL4 explained

ATP-dependent DNA helicase Q4 is an enzyme that in humans is encoded by the RECQL4 gene.^{[1] [2] [3]}

Mutations in RECQL4 are associated with the autosomal recessive disease Rothmund–Thomson syndrome, a disorder that has features of premature aging.^{[4] [5]} In addition to the Rothmund–Thomson syndrome, RECQL4 mutations are also associated with RAPADILINO and Baller–Gerold syndromes.^[6] There are two types of Rothmund Thomson syndrome and it is Type 2 that occurs in patients carrying deleterious mutations in both copies of the RECQL4 gene. This condition is associated with a high risk of developing osteosarcoma (malignant tumor of the bone).^[7] RECQL4 gets its name from being homologous (sharing sequence) with other members of the RecQ helicase family. Two other genetic diseases are due to mutations in other RECQ helicases. Bloom syndrome is associated with mutations in the BLM gene and Werner syndrome is associated with mutations in the WRN gene.^[8]

DNA repair

Double-strand breaks in DNA are potentially lethal to a cell and need to be repaired. Repair of double-strand breaks by homologous recombination (HR) is an important cellular mechanism for avoiding this lethality. RECQL4 has a crucial role in the first step of HR, referred to as end resection.^[9] When RECQL4 is deficient, end resection, and thus HR, is reduced. Evidence suggests that other forms of DNA repair including non-homologous end joining, nucleotide excision repair and base excision repair also depend on RECQL4 function. In the Rothmund-Thomson syndrome, the association of deficient RECQL4-mediated DNA repair and premature aging is consistent with the DNA damage theory of aging.

Further reading

• Kellermayer R . The versatile RECQL4. . Genet. Med. . 8 . 4 . 213–6 . 2006 . 16617241 . 10.1097/01.gim.0000214457.58378.1a . free .
• Soukup T . Intrafusal fibre types in rat limb muscle spindles: morphological and histochemical characteristics. . Histochemistry . 47 . 1 . 43–57 . 1976 . 133085 . 10.1007/BF00492992 . 23487130 .
• Kitao S, Shimamoto A, Goto M, etal . Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. . Nat. Genet. . 22 . 1 . 82–4 . 1999 . 10319867 . 10.1038/8788 . 195211275 .
• Yankiwski V, Marciniak RA, Guarente L, Neff NF . Nuclear structure in normal and Bloom syndrome cells. . Proc. Natl. Acad. Sci. U.S.A. . 97 . 10 . 5214–9 . 2000 . 10779560 . 10.1073/pnas.090525897 . 25808 . 2000PNAS...97.5214Y . free .
• Kawabe T, Tsuyama N, Kitao S, etal . Differential regulation of human RecQ family helicases in cell transformation and cell cycle. . Oncogene . 19 . 41 . 4764–72 . 2000 . 11032027 . 10.1038/sj.onc.1203841 . free .
• Wang LL, Worley K, Gannavarapu A, etal . Intron-size constraint as a mutational mechanism in Rothmund-Thomson syndrome. . Am. J. Hum. Genet. . 71 . 1 . 165–7 . 2002 . 12016592 . 10.1086/341234 . 384974 .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Roversi G, Beghini A, Zambruno G, etal . Identification of two novel RECQL4exonic SNPs and genomic characterization of the IVS12 minisatellite. . J. Hum. Genet. . 48 . 2 . 107–9 . 2003 . 12601557 . 10.1007/s100380300016 . 9960752 . free .
• Wang LL, Gannavarapu A, Clericuzio CL, etal . Absence of RECQL4 mutations in poikiloderma with neutropenia in Navajo and non-Navajo patients. . Am. J. Med. Genet. A . 118 . 3 . 299–301 . 2004 . 12673665 . 10.1002/ajmg.a.10057 . 36023058 .
• Beghini A, Castorina P, Roversi G, etal . RNA processing defects of the helicase gene RECQL4 in a compound heterozygous Rothmund-Thomson patient. . Am. J. Med. Genet. A . 120 . 3 . 395–9 . 2004 . 12838562 . 10.1002/ajmg.a.20154 . 25885145 .
• Siitonen HA, Kopra O, Kääriäinen H, etal . Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases. . Hum. Mol. Genet. . 12 . 21 . 2837–44 . 2004 . 12952869 . 10.1093/hmg/ddg306 . free .
• Brandenberger R, Wei H, Zhang S, etal . Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. . Nat. Biotechnol. . 22 . 6 . 707–16 . 2005 . 15146197 . 10.1038/nbt971 . 27764390 .
• Nishijo K, Nakayama T, Aoyama T, etal . Mutation analysis of the RECQL4 gene in sporadic osteosarcomas. . Int. J. Cancer . 111 . 3 . 367–72 . 2004 . 15221963 . 10.1002/ijc.20269 . 20389854 . free .
• Yin J, Kwon YT, Varshavsky A, Wang W . RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway. . Hum. Mol. Genet. . 13 . 20 . 2421–30 . 2005 . 15317757 . 10.1093/hmg/ddh269 . free .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Sengupta S, Shimamoto A, Koshiji M, etal . Tumor suppressor p53 represses transcription of RECQ4 helicase. . Oncogene . 24 . 10 . 1738–48 . 2005 . 15674334 . 10.1038/sj.onc.1208380 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Rothmund-Thomson Syndrome

Notes and References

1. Kitao S, Ohsugi I, Ichikawa K, Goto M, Furuichi Y, Shimamoto A . Cloning of two new human helicase genes of the RecQ family: biological significance of multiple species in higher eukaryotes . Genomics . 54 . 3 . 443–52 . Feb 1999 . 9878247 . 10.1006/geno.1998.5595 .
2. Sangrithi MN, Bernal JA, Madine M, Philpott A, Lee J, Dunphy WG, Venkitaraman AR . Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome . Cell . 121 . 6 . 887–98 . Jun 2005 . 15960976 . 10.1016/j.cell.2005.05.015 . 15064074 . free .
3. Web site: Entrez Gene: RECQL4 RecQ protein-like 4.
4. Lu H, Fang EF, Sykora P, Kulikowicz T, Zhang Y, Becker KG, Croteau DL, Bohr VA . Senescence induced by RECQL4 dysfunction contributes to Rothmund–Thomson syndrome features in mice . Cell Death Dis . 5 . 5. e1226 . 2014 . 24832598 . 4047874 . 10.1038/cddis.2014.168 .
5. Lu L, Jin W, Wang LL . Aging in Rothmund-Thomson syndrome and related RECQL4 genetic disorders . Ageing Res. Rev. . 33 . 30–35 . 2017 . 27287744 . 10.1016/j.arr.2016.06.002 . 28321025 .
6. Shamanna RA, Singh DK, Lu H, Mirey G, Keijzers G, Salles B, Croteau DL, Bohr VA . RECQ helicase RECQL4 participates in non-homologous end joining and interacts with the Ku complex . Carcinogenesis . 35 . 11 . 2415–24 . 2014 . 24942867 . 4216052 . 10.1093/carcin/bgu137 .
7. Wang LL, Gannavarapu A, Kozinetz CA, etal . Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. . J. Natl. Cancer Inst. . 95 . 9 . 669–74 . 2003 . 12734318 . 10.1093/jnci/95.9.669 . free .
8. Kitao S, Lindor NM, Shiratori M, etal . Rothmund-thomson syndrome responsible gene, RECQL4: genomic structure and products. . Genomics . 61 . 3 . 268–76 . 2000 . 10552928 . 10.1006/geno.1999.5959 .
9. Lu H, Shamanna RA, Keijzers G, Anand R, Rasmussen LJ, Cejka P, Croteau DL, Bohr VA . RECQL4 Promotes DNA End Resection in Repair of DNA Double-Strand Breaks . Cell Rep . 16 . 1 . 161–73 . 2016 . 27320928 . 5576896 . 10.1016/j.celrep.2016.05.079 .