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Pathogenic NAP57 mutations decrease ribonucleoprotein assembly in dyskeratosis congenita.

ABSTRACT: 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.

SUBMITTER: Grozdanov PN

PROVIDER: S-EPMC2773269 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Pathogenic NAP57 mutations decrease ribonucleoprotein assembly in dyskeratosis congenita.

Grozdanov Petar N PN Fernandez-Fuentes Narcis N Fiser Andras A Meier U Thomas UT

Human molecular genetics 20090904 23

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-ter ...[more]

PMID: 19734544

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