Poly(ADP-Ribose) Regulates Stress Responses and MicroRNA Activity in the Cytoplasm

SummaryPoly(ADP-ribose) is a major regulatory macromolecule in the nucleus, where it regulates transcription, chromosome structure, and DNA damage repair. Functions in the interphase cytoplasm are less understood. Here, we identify a requirement for poly(ADP-ribose) in the assembly of cytoplasmic stress granules, which accumulate RNA-binding proteins that regulate the translation and stability of mRNAs upon stress. We show that poly(ADP-ribose), six specific poly(ADP-ribose) polymerases, and two poly(ADP-ribose) glycohydrolase isoforms are stress granule components. A subset of stress granule proteins, including microRNA-binding Argonaute family members Ago1–4, are modified by poly(ADP-ribose), and such modification increases upon stress, a condition when both microRNA-mediated translational repression and microRNA-directed mRNA cleavage are relieved. Similar relief of repression is also observed upon overexpression of specific poly(ADP-ribose) polymerases or, conversely, upon knockdown of glycohydrolase. We conclude that poly(ADP-ribose) is a key regulator of posttranscriptional gene expression in the cytoplasm.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (263 K)Download as PowerPoint slideHighlights► Upon stress, poly(ADP-ribose) is enriched in stress granules in the cytoplasm ► Specific PARPs and PARG isoforms localize to and regulate stress granule integrity ► Poly(ADP-ribose) modifies cytoplasmic proteins, including miRNA-binding Argonautes ► Overexpression of PARP-13 or knockdown of PARG attenuates miRNA-mediated silencing