Differential stability of thymidylate synthase 3'-untranslated region polymorphic variants regulated by AUF1.
A 6-nucleotide insertion (I)/deletion (D) polymorphism in the 3'-untranslated region of the thymidylate synthase gene was shown to influence mRNA stability, but the molecular basis of this effect has not been elucidated. Here, studies of both endogenous and ectopically expressed thymidylate synthase alleles revealed that the mRNA-binding, decay-promoting protein AUF1 has higher affinity for allele D mRNA. AUF1 overexpression preferentially suppressed D allele mRNA levels, whereas AUF1 silencing selectively elevated D allele mRNA levels. Our results illustrate the functional consequences of ribonucleoprotein associations involving a polymorphic RNA sequence and uncover a novel mechanism of action for non-coding RNA polymorphisms.
Pullmann
Rudolf
R
Laboratory of Cellular and Molecular Biology, NIA-IRP, National Institutes of Health, Baltimore, Maryland 21224, USA. pullmannru@nih.gov
Abdelmohsen
Kotb
K
Lal
Ashish
A
Martindale
Jennifer L
JL
Ladner
Robert D
RD
Gorospe
Myriam
M
D020413:3' Untranslated Regions / Q000235:genetics*; D000483:Alleles; D001483:Base Sequence; D045744:Cell Line, Tumor; D004795:Enzyme Stability / Q000235:genetics; D020868:Gene Silencing; D014644:Genetic Variation; D006367:HeLa Cells; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
D020413:3' Untranslated Regions; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D012333:RNA, Messenger; D013940:Thymidylate Synthase