Human Molecular Genetics Advance Access originally published online on September 4, 2009
Human Molecular Genetics 2009 18(23):4546-4551; doi:10.1093/hmg/ddp416
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Pathogenic NAP57 mutations decrease ribonucleoprotein assembly in dyskeratosis congenita
1 Department of Anatomy and Structural Biology, 2 Department of Systems and Computational Biology and 3 Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
* To whom correspondence should be addressed. Tel: +1 7184303294; Fax: +1 7184308996; Email: meier{at}aecom.yu.edu
Received July 20, 2009; Revised August 13, 2009; Accepted August 26, 2009
X-linked dyskeratosis congenita (DC) is a rare bone marrow failure syndrome caused by mostly missense mutations in the pseudouridine synthase NAP57 (dyskerin/Cbf5). As part of H/ACA ribonucleoproteins (RNPs), NAP57 is important for the biogenesis of ribosomes, spliceosomal small nuclear RNPs, microRNAs and the telomerase RNP. DC mutations concentrate in the N- and C-termini of NAP57 but not in its central catalytic domain raising questions as to their impact. We demonstrate that the N- and C-termini together form the binding surface for the H/ACA RNP assembly factor SHQ1 and that DC mutations modulate the interaction between the two proteins. Pinpointing impaired interaction between NAP57 and SHQ1 as a potential molecular basis for X-linked DC has implications for therapeutic approaches, e.g. by targeting the NAP57–SHQ1 interface with small molecules.
Present address: Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
Present address: Leeds Institute of Molecular Medicine, Section of Experimental Therapeutics, University of Leeds, St James's University Hospital, Wellcome Trust Brenner Building, Leeds LS9 7TF, UK.