mRNA and DNA selection via protein multimerization: YB-1 as a case study

Abstract

Translation is tightly regulated in cells for keeping adequate protein levels, this task being notably accomplished by dedicated mRNA-binding proteins recognizing a specific set of mRNAs to repress or facilitate their translation. To select specific mRNAs, mRNA-binding proteins can strongly bind to specific mRNA sequences/structures. However, many mRNA-binding proteins rather display a weak specificity to short and redundant sequences. Here we examined an alternative mechanism by which mRNA-binding proteins could inhibit the translation of specific mRNAs, using YB-1, a major translation regulator, as a case study. Based on a cooperative binding, YB-1 forms stable homo-multimers on some mRNAs while avoiding other mRNAs. Via such inhomogeneous distribution, YB-1 can selectively inhibit translation of mRNAs on which it has formed stable multimers. This novel mechanistic view on mRNA selection may be shared by other proteins considering the elevated occurrence of multimerization among mRNA-binding proteins. Interestingly, we also demonstrate how, by using the same mechanism, YB-1 can form multimers on specific DNA structures, which could provide novel insights into YB-1 nuclear functions in DNA repair and multi-drug resistance.

Y-Box Binding Proteins in mRNP Assembly, Translation, and Stability Control

“…Interestingly, the interaction between YB proteins and DNA strongly depends on the integrity of the DNA secondary structure [29,43,44,59,60]. In addition, as shown recently by atomic force microscopy (AFM), YB-1 binds preferentially to supercoiled DNA at DNA crosses [61].…”

“…Their amount can even increase due to many vacant binding sites on the mRNA. As calculated in [61], the entire amount of YB-1 in the cell would be sufficient to completely package only a small fraction of mRNA molecules. It can be assumed that YB-1 participates in the formation of untranslated mRNPs due to multimerization occurring only on specific mRNAs [61], while on the others, its amount is lower.…”

“…As calculated in [61], the entire amount of YB-1 in the cell would be sufficient to completely package only a small fraction of mRNA molecules. It can be assumed that YB-1 participates in the formation of untranslated mRNPs due to multimerization occurring only on specific mRNAs [61], while on the others, its amount is lower. Alternatively, although present in large amounts [95], YB proteins are far from being the only participants of the packaging of both translated and untranslated mRNPs.…”

At the Interface of Three Nucleic Acids: The Role of RNA-Binding Proteins and Poly(ADP-ribose) in DNA Repair

“…The bulk of the YB-1 structure is natively unfolded [167], which facilitates interaction promiscuity and confers the ability to self-aggregate, allowing for multimerization in the presence of RNA and DNA [182] or the formation of amyloid fibrils at a high ionic strength [183]. YB-1 binds to a wide range of DNA repair enzymes: base excision repair enzymes (NEIL2 [177], APE1 [184], DNA polymerase β [177], DNA polymerase δ [185], PCNA [186], DNA-ligase IIIα [177], NEIL1, PARP1, and PARP2 [187]), mismatch repair enzymes (MSH2 [185]), and DNA double-stranded breaks repair enzymes (Ku80 [185]).…”

Secreted protein YB-1 and its prognostic significance

“…YB-1 проявляет свойства шаперона нуклеиновых кис-лот и взаимодействует с большим количеством других белков. Взаимодействуя с нуклеиновыми кислотами, YB-1 принимает участие практически во всех процес-сах, зависимых от ДНК и матричной РНК (мРНК), включая репликацию и репарацию ДНК, транскрип-цию, сплайсинг и трансляцию мРНК [8][9][10]. Он упа-ковывает и стабилизирует мРНК и осуществляет гло-бальную и специфическую регуляцию экспрессии генов на различных уровнях [7,11].…”