ATP-dependent helicase activity is dispensable for the physiological functions of Recql4

PLoS Genet. 2019 Jul 5;15(7):e1008266. doi: 10.1371/journal.pgen.1008266. eCollection 2019 Jul.


Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by skin rash (poikiloderma), skeletal dysplasia, small stature, juvenile cataracts, sparse or absent hair, and predisposition to specific malignancies such as osteosarcoma and hematological neoplasms. RTS is caused by germ-line mutations in RECQL4, a RecQ helicase family member. In vitro studies have identified functions for the ATP-dependent helicase of RECQL4. However, its specific role in vivo remains unclear. To determine the physiological requirement and the biological functions of Recql4 helicase activity, we generated mice with an ATP-binding-deficient knock-in mutation (Recql4K525A). Recql4K525A/K525A mice were strikingly normal in terms of embryonic development, body weight, hematopoiesis, B and T cell development, and physiological DNA damage repair. However, mice bearing two distinct truncating mutations Recql4G522Efs and Recql4R347*, that abolished not only the helicase but also the C-terminal domain, developed a profound bone marrow failure and decrease in survival similar to a Recql4 null allele. These results demonstrate that the ATP-dependent helicase activity of Recql4 is not essential for its physiological functions and that other domains might contribute to this phenotype. Future studies need to be performed to elucidate the complex interactions of RECQL4 domains and its contribution to the development of RTS.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • B-Lymphocytes / metabolism
  • Binding Sites
  • Body Weight
  • DNA Damage
  • Disease Models, Animal
  • Embryonic Development
  • Gene Knock-In Techniques
  • Hematopoiesis
  • Humans
  • Mice
  • Phenotype
  • Protein Domains
  • RecQ Helicases / chemistry
  • RecQ Helicases / genetics*
  • RecQ Helicases / metabolism*
  • Rothmund-Thomson Syndrome / genetics*
  • T-Lymphocytes / metabolism


  • Adenosine Triphosphate
  • RecQ Helicases
  • Recql4 protein, mouse

Grants and funding

This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Cancer Research under Award No. W81XWH-15-1-0315 (to CRW). Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense (USA); National Health and Medical Research Council Australia project grant (NHMRC; CRW and AJD, APP1102004); a Melbourne Research Scholarship (WCT, University of Melbourne); Victorian Cancer Agency Research Fellowship (CRW, MCRF15015; AJD, MCRF15024); This work was enabled by the Australian Phenomics Network and partly supported by funding from the Australian Government’s National Collaborative Research Infrastructure Strategy and the Super Science Initiative through the Education Investment Fund (to Australian Phenomics Network); and in part by the Victorian State Government Operational Infrastructure Support (to St Vincent’s Institute). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.