RecQ helicase

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Bloom syndrome
Other data
LocusChr. 15 [1]
RecQ protein-like 4
Other data
LocusChr. 8 q24.3
RecQ protein-like 5
Other data
LocusChr. 17 q25
RMI1, RecQ mediated genome instability 1
Alt. symbolsC9orf76
Other data
LocusChr. 9 q22.1
Werner syndrome
Other data
LocusChr. 8 p

RecQ helicase is a family of helicase enzymes initially found in Escherichia coli[1] that has been shown to be important in genome maintenance.[2][3][4] They function through catalyzing the reaction ATP + H2O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H2O → NDP + P to drive the unwinding of either DNA or RNA.


In prokaryotes RecQ is necessary for plasmid recombination and DNA repair from UV-light, free radicals, and alkylating agents. This protein can also reverse damage from replication errors. In eukaryotes, replication does not proceed normally in the absence of RecQ proteins, which also function in aging, silencing, recombination and DNA repair.


RecQ family members share three regions of conserved protein sequence referred to as the:

  • N-terminal – Helicase
  • middle – RecQ-conserved (RecQ-Ct) and
  • C-terminal – Helicase-and-RNase-D C-terminal (HRDC) domains.

The removal of the N-terminal residues (Helicase and, RecQ-Ct domains) impairs both helicase and ATPase activity but has no effect on the binding ability of RecQ implying that the N-terminus functions as the catalytic end. Truncations of the C-terminus (HRDC domain) compromise the binding ability of RecQ but not the catalytic function. The importance of RecQ in cellular functions is exemplified by human diseases, which all lead to genomic instability and a predisposition to cancer.

Clinical significance

There are at least five human RecQ genes; and mutations in three human RecQ genes are implicated in heritable human diseases: WRN gene in Werner syndrome (WS), BLM gene in Bloom syndrome (BS), and RECQ4 in Rothmund-Thomson syndrome.[5] These syndromes are characterized by premature aging, and can give rise to the diseases of cancer, type 2 diabetes, osteoporosis, and atherosclerosis, which are commonly found in old age. These diseases are associated with high incidence of chromosomal abnormalities, including chromosome breaks, complex rearrangements, deletions and translocations, site specific mutations, and in particular sister chromatid exchanges (more common in BS) that are believed to be caused by a high level of somatic recombination.


The proper function of RecQ helicases requires the specific interaction with topoisomerase III (Top 3). Top 3 changes the topological status of DNA by binding and cleaving single stranded DNA and passing either a single stranded or a double stranded DNA segment through the transient break and finally religating the break. The interaction of RecQ helicase with topoisomerase III at the N-terminal region is involved in the suppression of spontaneous and damage induced recombination and the absence of this interaction results in a lethal or very severe phenotype. The emerging picture clearly is that RecQ helicases in concert with Top 3 are involved in maintaining genomic stability and integrity by controlling recombination events, and repairing DNA damage in the G2-phase of the cell cycle. The importance of RecQ for genomic integrity is exemplified by the diseases that arise as a consequence of mutations or malfunctions in RecQ helicases; thus it is crucial that RecQ is present and functional to ensure proper human growth and development.

WRN helicase

The Werner syndrome ATP-dependent helicase (WRN helicase) is unusual among RecQ DNA family helicases in having an additional exonuclease activity. WRN interacts with DNA-PKcs and the Ku protein complex. This observation, combined with evidence that WRN deficient cells produce extensive deletions at sites of joining of non-homologous DNA ends, suggests a role for WRN protein in the DNA repair process of non-homologous end joining (NHEJ).[6] WRN also physically interacts with the major NHEJ factor X4L4 (XRCC4-DNA ligase 4 complex).[7] X4L4 stimulates WRN exonuclease activity that likely facilitates DNA end processing prior to final ligation by X4L4.[7]

WRN also appears to play a role in resolving recombination intermediate structures during homologous recombinational repair (HRR) of DNA double-strand breaks.[6]

WRN participates in a complex with RAD51, RAD54, RAD54B and ATR proteins in carrying out the recombination step during inter-strand DNA cross-link repair.[8]

Evidence was presented that WRN plays a direct role in the repair of methylation induced DNA damage. The process likely involves the helicase and exonuclease activities of WRN that operate together with DNA polymerase beta in long patch base excision repair.[9]

WRN was found to have a specific role in preventing or repairing DNA damages resulting from chronic oxidative stress, particularly in slowly replicating cells.[10] This finding suggested that WRN may be important in dealing with oxidative DNA damages that underlie normal aging[10] (see DNA damage theory of aging).

BLM helicase

Cells from humans with Bloom syndrome are sensitive to DNA damaging agents such as UV and methyl methanesulfonate[11] indicating deficient DNA repair capability.

The budding yeast Saccharomyces cerevisiae encodes an ortholog of the Bloom syndrome (BLM) protein that is designated Sgs1 (Small growth suppressor 1). Sgs1(BLM) is a helicase that functions in homologous recombinational repair of DNA double-strand breaks. The Sgs1(BLM) helicase appears to be a central regulator of most of the recombination events that occur during S. cerevisiae meiosis.[12] During normal meiosis Sgs1(BLM) is responsible for directing recombination towards the alternate formation of either early non-crossovers or Holliday junction joint molecules, the latter being subsequently resolved as crossovers.[12]

In the plant Arabidopsis thaliana, homologs of the Sgs1(BLM) helicase act as major barriers to meiotic crossover formation.[13] These helicases are thought to displace the invading strand allowing its annealing with the other 3’overhang end of the double-strand break, leading to non-crossover recombinant formation by a process called synthesis-dependent strand annealing (SDSA) (see Wikipedia article “Genetic recombination”). It is estimated that only about 5% of double-strand breaks are repaired by crossover recombination. Sequela-Arnaud et al.[13] suggested that crossover numbers are restricted because of the long-term costs of crossover recombination, that is, the breaking up of favorable genetic combinations of alleles built up by past natural selection.

RECQL4 helicase

In humans, individuals with Rothmund-Thomson syndrome, and carrying the RECQL4 germline mutation, have several clinical features of accelerated aging. These features include atrophic skin and pigment changes, alopecia, osteopenia, cataracts and an increased incidence of cancer.[14] RECQL4 mutant mice also show features of accelerated aging.[15]

RECQL4 has a crucial role in DNA end resection that is the initial step required for homologous recombination (HR)-dependent double-strand break repair.[16] When RECQL4 is depleted, HR-mediated repair and 5’ end resection are severely reduced in vivo. RECQL4 also appears to be necessary for other forms of DNA repair including non-homologous end joining, nucleotide excision repair and base excision repair.[14] The association of deficient RECQL4 mediated DNA repair with accelerated aging is consistent with the DNA damage theory of aging.

See also


  1. Bernstein DA, Keck JL (June 2003). "Domain mapping of Escherichia coli RecQ defines the roles of conserved N- and C-terminal regions in the RecQ family". Nucleic Acids Res. 31 (11): 2778–85. doi:10.1093/nar/gkg376. PMC 156711. PMID 12771204.
  2. Cobb JA, Bjergbaek L, Gasser SM (October 2002). "RecQ helicases: at the heart of genetic stability". FEBS Lett. 529 (1): 43–8. doi:10.1016/S0014-5793(02)03269-6. PMID 12354611.
  3. Kaneko H, Fukao T, Kondo N (2004). "The function of RecQ helicase gene family (especially BLM) in DNA recombination and joining". Adv. Biophys. 38: 45–64. doi:10.1016/S0065-227X(04)80061-3. PMID 15493327.
  4. Ouyang KJ, Woo LL, Ellis NA (2008). "Homologous recombination and maintenance of genome integrity: cancer and aging through the prism of human RecQ helicases". Mech. Ageing Dev. 129 (7–8): 425–40. doi:10.1016/j.mad.2008.03.003. PMID 18430459.
  5. Hanada K, Hickson ID (September 2007). "Molecular genetics of RecQ helicase disorders". Cell. Mol. Life Sci. 64 (17): 2306–22. doi:10.1007/s00018-007-7121-z. PMID 17571213.
  6. 6.0 6.1 Thompson LH, Schild D (2002). "Recombinational DNA repair and human disease". Mutat. Res. 509 (1–2): 49–78. doi:10.1016/s0027-5107(02)00224-5. PMID 12427531.
  7. 7.0 7.1 Kusumoto R, Dawut L, Marchetti C, Wan Lee J, Vindigni A, Ramsden D, Bohr VA (2008). "Werner protein cooperates with the XRCC4-DNA ligase IV complex in end-processing". Biochemistry. 47 (28): 7548–56. doi:10.1021/bi702325t. PMC 2572716. PMID 18558713.
  8. Otterlei M, Bruheim P, Ahn B, Bussen W, Karmakar P, Baynton K, Bohr VA (2006). "Werner syndrome protein participates in a complex with RAD51, RAD54, RAD54B and ATR in response to ICL-induced replication arrest". J. Cell Sci. 119 (Pt 24): 5137–46. doi:10.1242/jcs.03291. PMID 17118963.
  9. Harrigan JA, Wilson DM, Prasad R, Opresko PL, Beck G, May A, Wilson SH, Bohr VA (2006). "The Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase beta". Nucleic Acids Res. 34 (2): 745–54. doi:10.1093/nar/gkj475. PMC 1356534. PMID 16449207.
  10. 10.0 10.1 Szekely AM, Bleichert F, Nümann A, Van Komen S, Manasanch E, Ben Nasr A, Canaan A, Weissman SM (2005). "Werner protein protects nonproliferating cells from oxidative DNA damage". Mol. Cell. Biol. 25 (23): 10492–506. doi:10.1128/MCB.25.23.10492-10506.2005. PMC 1291253. PMID 16287861.
  11. So S, Adachi N, Lieber MR, Koyama H (2004). "Genetic interactions between BLM and DNA ligase IV in human cells". J. Biol. Chem. 279 (53): 55433–42. doi:10.1074/jbc.M409827200. PMID 15509577.
  12. 12.0 12.1 De Muyt A, Jessop L, Kolar E, Sourirajan A, Chen J, Dayani Y, Lichten M (2012). "BLM helicase ortholog Sgs1 is a central regulator of meiotic recombination intermediate metabolism". Mol. Cell. 46 (1): 43–53. doi:10.1016/j.molcel.2012.02.020. PMC 3328772. PMID 22500736.
  13. 13.0 13.1 Séguéla-Arnaud M, Crismani W, Larchevêque C, Mazel J, Froger N, Choinard S, Lemhemdi A, Macaisne N, Van Leene J, Gevaert K, De Jaeger G, Chelysheva L, Mercier R (2015). "Multiple mechanisms limit meiotic crossovers: TOP3α and two BLM homologs antagonize crossovers in parallel to FANCM". Proc. Natl. Acad. Sci. U.S.A. 112 (15): 4713–8. doi:10.1073/pnas.1423107112. PMC 4403193. PMID 25825745.
  14. 14.0 14.1 Lu L, Jin W, Wang LL (2017). "Aging in Rothmund-Thomson syndrome and related RECQL4 genetic disorders". Ageing Res. Rev. 33: 30–35. doi:10.1016/j.arr.2016.06.002. PMID 27287744.
  15. Lu H, Fang EF, Sykora P, Kulikowicz T, Zhang Y, Becker KG, Croteau DL, Bohr VA (2014). "Senescence induced by RECQL4 dysfunction contributes to Rothmund-Thomson syndrome features in mice". Cell Death Dis. 5: e1226. doi:10.1038/cddis.2014.168. PMC 4047874. PMID 24832598.
  16. Lu H, Shamanna RA, Keijzers G, Anand R, Rasmussen LJ, Cejka P, Croteau DL, Bohr VA (2016). "RECQL4 Promotes DNA End Resection in Repair of DNA Double-Strand Breaks". Cell Rep. 16 (1): 161–73. doi:10.1016/j.celrep.2016.05.079. PMID 27320928.

Further reading

  • Skouboe C, Bjergbaek L, Andersen AH (2005). "Genome instability as a cause of ageing and cancer: Implications of RecQ helicases". Signal Transduction. 5 (3): 142–151. doi:10.1002/sita.200400052.
  • Laursen LV, Bjergbaek L, Murray JM, Andersen AH (2003). "RecQ helicases and topoisomerase III in cancer and aging". Biogerontology. 4 (5): 275–87. doi:10.1023/A:1026218513772. PMID 14618025.

External links