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

Abstract

RNA-binding proteins (RBPs) regulate RNA metabolism, from synthesis to decay. When bound to RNA, RBPs act as guardians of the genome integrity at different levels, from DNA damage prevention to the post-transcriptional regulation of gene expression. Recently, RBPs have been shown to participate in DNA repair. This fact is of special interest as DNA repair pathways do not generally involve RNA. DNA damage in higher organisms triggers the formation of the RNA-like polymer - poly(ADP-ribose) (PAR). Nucleic acid-like properties allow PAR to recruit DNA- and RNA-binding proteins to the site of DNA damage. It is suggested that poly(ADP-ribose) and RBPs not only modulate the activities of DNA repair factors, but that they also play an important role in the formation of transient repairosome complexes in the nucleus. Cytoplasmic biomolecules are subjected to similar sorting during the formation of RNA assemblages by functionally related mRNAs and promiscuous RBPs. The Y-box-binding protein 1 (YB-1) is the major component of cytoplasmic RNA granules. Although YB-1 is a classic RNA-binding protein, it is now regarded as a non-canonical factor of DNA repair.

Keywords: DNA repair; RNA-binding proteins; Y-box-binding protein 1; intrinsically disordered proteins; poly(ADP-ribose).

Fig. 1

Eukaryotic RNA operons (schematic representation) 1 – nucleus; 2 – pre-mRNA; 3 – RNA-binding proteins; 4 – cytoplasmic RNA granules (RNA operons); 5 – ribosome. The figure schematically shows the formation and functioning of cytoplasmic RNA assemblages. These complexes of functionally related mRNAs and RBPs act as RNA operons that facilitate the synchronous translation of proteins involved in the same biochemical pathway

Fig. 2

Phase transitions of biomolecules 1 – functional membraneless organelles; 2 – pathological amyloid aggregates of proteins. Cellular biomolecules undergo phase transitions as water does. In the gaseous state, biomolecules are dispersed throughout the cell and do not interact with each other. A local increase in the concentration of promiscuous and intrinsically disordered proteins results in intracellular liquid demixing and induces the assembly of membraneless compartments that have liquid-like properties [30-32]. The liquid-like state is maintained by multiple weak interactions among the interaction partners. An irreversible transition into a condensed liquid state appears to lead to amyloid fibers that are associated with such disorders as Alzheimer’s disease [35]

Fig. 3

PARP1- dependent DNA damage signaling (schematic representation)

Fig. 4

Switching of YB-1 cellular functions upon genotoxic stress (schematic representation) 1 – nucleus; 2 – DNA damage; 3 – DNA repair enzyme; 4 – poly(ADP-ribose); 5 – cytoplasmic RNA granule; 6 – ribosome