Abstract
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.
Highlights
Rothmund-Thomson syndrome (RTS) (OMIM #268400) is a rare autosomal recessive disorder characterized by skin rash, skeletal dysplasia, small stature, sparse or absent hair, gastrointestinal complications, and high predisposition to specific malignancies such as osteosarcoma (OS) and hematological neoplasms [1, 2]
RECQL4 is a member of this family and its mutation results in Rothmund-Thomson syndrome (RTS)
Prior studies have shown that defects in the helicase region of RECQL4 may contribute to the disease, but no studies have assessed the biological effects of its absence in a whole animal model
Summary
Rothmund-Thomson syndrome (RTS) (OMIM #268400) is a rare autosomal recessive disorder characterized by skin rash (poikiloderma), skeletal dysplasia, small stature, sparse or absent hair, gastrointestinal complications, and high predisposition to specific malignancies such as osteosarcoma (OS) and hematological neoplasms [1, 2]. Helicases are enzymes that unwind double-stranded or more complex DNA and RNA structures using energy from ATP hydrolysis. Mutations in three are associated with syndromes that present with premature aging and cancer-predisposition: WRN in Werner’s syndrome, BLM in Bloom’s syndrome, and RECQL4 in RTS [8, 9]. RECQL4 differs from the other family members as it has no HRDC domain and lacks a structurally conserved RQC domain. Instead, it contains the structurally unique domain called RecQ4-Zn2+-binding domain (R4ZBD) and, importantly, an N-terminal region of homology with the S. cerevisiae DNA replication initiation factor Sld2 [12, 13]. Sld is an essential protein required for activation of replication origins in yeast [14], and RECQL4 is the putative mammalian homologue
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