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PMID: 15302914 Published · epublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Destabilization of tetraplex structures of the fragile X repeat sequence (CGG)n is mediated by homolog-conserved domains in three members of the hnRNP family.

Nucleic acids research ·Vol. 32 ·No. 14 ·2004-00-00 ·Pages 4145-54

Khateb S, Weisman-Shomer P, Hershco I, Loeb LA, Fry M

Abstract

Hairpin or tetrahelical structures formed by a d(CGG)n sequence in the FMR1 gene are thought to promote expansion of the repeat tract. Subsequent to this expansion FMR1 is silenced and fragile X syndrome ensues. The injurious effects of d(CGG)n secondary structures may potentially be countered by agents that act to decrease their stability. We showed previously that the hnRNP-related protein CBF-A destabilized G'2 bimolecular tetraplex structures of d(CGG)n. Analysis of mutant proteins revealed that the CBF-A-conserved domains RNP11 and ATP/GTP binding box were sufficient and necessary for G'2 d(CGG)n disruption while the RNP21 motif inhibited the destabilization activity. Here, we report that a C-terminal fragment of CBF-A whose only remaining conserved domain was the ATP/GTP binding motif, disrupted G'2 d(CGG)n more selectively than wild-type CBF-A. Further, two additional members of the hnRNP family, hnRNP A2 and mutant hnRNP A1 effectively destabilized G'2 d(CGG)n. Examination of mutant hnRNP A2 proteins revealed that, similar to CBF-A, their RNP11 element and ATP/GTP binding motif mediated G'2 d(CGG)n disruption, while the RNP21 element blocked their action. Similarly, the RNP11 and RNP21 domains of hnRNP A1 were, respectively, positive and negative mediators of G'2 d(CGG)n destabilization. Last, employing the same conserved motifs that mediated disruption of the DNA tetraplex G'2 d(CGG)n, hnRNP A2 destabilized r(CGG)n RNA tetraplex.

MeSH Terms
Adenosine Triphosphate/metabolism Amino Acid Motifs Amino Acid Sequence Binding Sites Conserved Sequence DNA/chemistry Fragile X Mental Retardation Protein G-Quadruplexes Guanosine Triphosphate/metabolism Heterogeneous Nuclear Ribonucleoprotein A1 Heterogeneous-Nuclear Ribonucleoprotein Group A-B/chemistry,metabolism Molecular Sequence Data Nerve Tissue Proteins/genetics Nucleic Acid Conformation Protein Structure, Tertiary RNA/chemistry RNA Stability RNA-Binding Proteins Repetitive Sequences, Nucleic Acid Sequence Homology, Amino Acid
Chemicals
Heterogeneous Nuclear Ribonucleoprotein A1 Heterogeneous-Nuclear Ribonucleoprotein Group A-B Nerve Tissue Proteins RNA-Binding Proteins hnRNP A2 Fragile X Mental Retardation Protein RNA Guanosine Triphosphate Adenosine Triphosphate DNA
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Khateb Samer
Unit of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9649, Haifa 31096, Israel.
Weisman-Shomer Pnina
Hershco Inbal
Loeb Lawrence A
Fry Michael
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
DOI
10.1093/nar/gkh745
Published
2004-00-00
Epub
2004-00-09
Pages
4145-54
Language
English
Region
England
NLM ID
0411011
PMCID
PMC514371
Subset
IM
Grants
NCI NIH HHS · P01 CA077852 · United States
NCI NIH HHS · CA77852 · United States
External Links
PubMed source DOI: 10.1093/nar/gkh745 PMC Full Text View journal details
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