Journal Article

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

Liu, Rui, Castillo-Tandazo, Wilson, Deans, Andrew J., Heierhorst, Jörg, Walkley, Carl R., Smeets, Monique F., Murphy, Vincent, Hodson, Charlotte

2019

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenosine Triphosphate - metabolism / Animals / ATPases / B cells / B-Lymphocytes - metabolism / Binding Sites / Biology and Life Sciences / Blood cancer / Body Weight / Bone cancer / Bone dysplasia / Bone marrow / Cataracts / Cell cycle / Childhood vision disorders / Deoxyribonucleic acid / Disease Models, Animal / DNA / DNA Damage / DNA helicase / DNA repair / Dysplasia / Embryogenesis / Embryonic Development / Future predictions / Gene Knock-In Techniques / Hematopoiesis / Hereditary diseases / Humans / Lymphocytes B / Lymphocytes T / Medical research / Medicine / Medicine and Health Sciences / Mice / Mutation / Osteosarcoma / Phenotype / Phenotypes / Physiological aspects / Physiology / Protein Domains / Proteins / Rash / RecQ Helicases - chemistry / RecQ Helicases - genetics / RecQ Helicases - metabolism / RecQ protein / Rothmund-Thomson syndrome / Rothmund-Thomson Syndrome - genetics / Sarcoma / Short stature / Skeleton / Skin / Skin diseases / Supervision / T cells / T-Lymphocytes - metabolism / Tumors