Open AccessATP-dependent helicase activity is dispensable for the physiological functions of Recql4
Author(s) -
Wilson Castillo-Tandazo,
Monique Smeets,
Vincent J. Murphy,
Rui Li,
Charlotte Hodson,
Jörg Heierhorst,
Andrew J. Deans,
Carl R. Walkley
Publication year - 2019
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1008266
Subject(s) - biology , helicase , genetics , rna helicase a , recq helicase , mutation , werner syndrome , dna repair , microbiology and biotechnology , phenotype , cancer research , dna , gene , rna
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 ( Recql4 K525A ). Recql4 K525A/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 Recql4 G522Efs and Recql4 R347* , 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.