Post-transcriptional regulation by poly(ADP-ribosyl)ation of the RNA-binding proteins

Abstract

Gene expression is intricately regulated at the post-transcriptional level by RNA-binding proteins (RBPs) via their interactions with pre-messenger RNA (pre-mRNA) and mRNA during development. However, very little is known about the mechanism regulating RBP activities in RNA metabolism. During the past few years, a large body of evidence has suggested that many RBPs, such as heterogeneous nuclear ribonucleoproteins (hnRNPs), undergo post-translational modification through poly(ADP-ribosyl)ation to modulate RNA processing, including splicing, polyadenylation, translation, miRNA biogenesis and rRNA processing. Accordingly, RBP poly(ADP-ribosyl)ation has been shown to be involved in stress responses, stem cell differentiation and retinal morphogenesis. Here, we summarize recent advances in understanding the biological roles of RBP poly(ADP-ribosyl)ation, as controlled by Poly(ADP-ribose) Polymerases (PARPs) and Poly(ADP-ribose) Glycohydrolase (PARG). In addition, we discuss the potential of PARP and PARG inhibitors for the treatment of RBP-related human diseases, including cancer and neurodegenerative disorders.

Figure 1

Nuclear Poly(ADP-ribose) turnover. Level of cellular pADPr reflects relative activities of the poly(ADP-ribose) polymerase (PARP) enzyme, which utilizes NAD to create pADPr-modified proteins, and the poly(ADP-Ribose) glycohydrolase (PARG) enzyme, which removes pADPr moieties. Arrowheads indicate cleavage sites of poly(ADP-ribose) by PARG.

Figure 2

Model explaining the regulatory role of RNA binding proteins (RBP) poly(ADP-ribosyl)ation. (A) In a temporal- or spatial-specific way, protein poly(ADP-ribosyl)ation is reversed by PARG activity. Therefore, RBPs bind only partially to poly(ADP-ribose) and will bind to their target heterogeneous nuclear RNAs (hnRNAs) for RNA processing or translational control; (B) Once PARG activity is downregulated (high PARP-1–low PARG activities) in different tissues or developmental stages, RBPs are poly(ADP-ribosyl)ated, which inhibits RBPs from binding to hnRNAs. Therefore, the hnRNA transcripts are not processed or translated, and developmental patterns are changed; (C) Downregulation of PARP-1 (low PARP-1–high PARG activities) leads to depletion of poly(ADP-ribose). Thus, all RBPs excessively bind to hnRNAs, altering processing and translation.

Figure 3

Diagram illustrating how hnRNP poly(ADP-ribosyl)ation controls maintenance of stem cells in the stem cell niche. HnRNP poly(ADP-ribosyl)ation regulates E-cadherin (E-Cad) translation: hnRNP binds to 5′UTR of E-cadherin to promote translation. Once hnRNP is poly(ADP-ribosyl)ated and dissociated from 5′UTR of E-cadherin, its translation is inhibited; Poly(ADP-ribosyl)ation of hnRNP controls germline stem cell maintenance: E-cadherin protein (red) accumulates between stem cell niche cells (Cap Cell) and stem cells, keeping stem cells in the niche. High level of poly(ADP-ribosyl)ation during mitosis and in cystoblasts suppresses translation of E-cadherin. Suppression of E-cadherin production promotes cystoblasts that have not established contacts with cap cells to leave the stem cell niche and differentiate.