Understanding a Novel Function of the poly(A) Tail in IRES-Mediated Translation of Cellular mRNAs

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Almost all eukaryotic mRNAs harbor a poly(A) tail which enhances cap dependent translation. Internal ribosomal entry sites (IRESs) have the remarkable ability to initiate translation independent of the capped 5¿ end. IRES elements are present in a variety of viral mRNAs and have also been identified in cellular transcripts. Recently, we discovered a new function of the poly(A) tail in cellular IRES-driven translation of the c-myc and BiP mRNAs: it enhances their IRES-driven translation by a mechanism that is distinct from how it activates cap-dependent translation. We obtained direct evidence that PABP is not the mediator of the poly (A) contribution to cellular IRES-driven translation indicating the possibility that (a) distinct factor(s) mediate(s) this enhancer function. Based on evidence outlined below, we propose to (1) purify and identify this (these) factor(s), (2) characterize its (their) function and its (their) interacting partners, and (3) investigate the underlying mechanism of the poly(A) enhancement of cellular IRESs.