Human Molecular Genetics Advance Access originally published online on August 18, 2004
Human Molecular Genetics 2004 13(20):2421-2430; doi:10.1093/hmg/ddh269
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Human Molecular Genetics, Vol. 13, No. 20 © Oxford University Press 2004; all rights reserved
RECQL4, mutated in the Rothmund–Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway
1Laboratory of Genetics, National Institute on Aging, National Institutes of Health, 333 Cassell Drive, TRIAD Center Room 3000, Baltimore, MD 21224, USA, 2Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA and 3Division of Biology, 147-75, California Institute of Technology, Pasadena, CA 91125, USA
Received May 6, 2004; Revised August 11, 2004; The Rothmund–Thomson syndrome (growth retardation, skin and bone defects, predisposition to cancer) and the RAPADILINO syndrome are caused by mutations in the RECQL4 gene. The 133 kDa RECQL4 is a putative DNA helicase, a member of the family that includes the BLM and WRN helicases. The latter are mutated, respectively, in the Bloom and Werner syndromes, whose manifestations include predisposition to cancer. Using antibodies to human RECQL4, we found that the bulk of RECQL4 was present in a cytoplasmic extract of HeLa cells, in contrast to the largely nuclear BLM and WRN helicases. However, in untransformed WI-38 fibroblasts, RECQL4 was found to be largely nuclear, and was present at significantly lower total levels than in transformed HeLa cells. RECQL4 from HeLa cells was isolated as a stable complex with UBR1 and UBR2. These 200 kDa proteins are ubiquitin ligases of the N-end rule pathway, whose substrates include proteins with destabilizing N-terminal residues. The functions of this proteolytic pathway include the regulation of peptide import, chromosome stability, meiosis, apoptosis and cardiovascular development. Although the known role of UBR1 and UBR2 is to mediate polyubiquitylation (and subsequent degradation) of their substrates, the UBR1/2-bound RECQL4 was not ubiquitylated in vivo, and was a long-lived protein in HeLa cells. The isolated RECQL4–UBR1/2 complex had a DNA-stimulated ATPase activity, but was inactive in DNA-based assays for helicases and translocases, the assays in which the BLM helicase was active. We discuss ramifications of these results, possible functions of RECQL4, and the involvement of the N-end rule pathway.
* To whom correspondence should be addressed. Tel: +1 4105588334; Fax: +1 4105588331; Email: wangw{at}grc.nia.nih.gov
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