Article

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

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Molecular cell (Impact Factor: 14.02). 05/2011; 42(4):489-99. DOI: 10.1016/j.molcel.2011.04.015
Source: PubMed

ABSTRACT

Poly(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.

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Available from: Anthony K. L. Leung, Apr 16, 2014
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    • "PARP family enzymes are involved in many physiological processes, including cell division, regulation of transcription, maintenance of telomere integrity, control of protein degradation, and cell survival and death [8, 9]. Additional important functions in cellular stress responses include detection of DNA damage, DNA repair, response to heat shock, response to unfolded protein in the endoplasmic reticulum, and the cytoplasmic stress response [6, 8, 10, 11]. Discovered more than 40 years ago, PARP1 is the founding member and the best characterized PARP [12, 13]. "
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    • "Our data support another function of the OGG1 that plays an important regulator during endotoxin-induced inflammatory response. The poly(ADPribose ) polymerase (PARP) is also a DNA repair enzyme with multifunctional activities, including chromatin remodeling, transcription, post-transcriptional gene expression, and cell death [42] [43] [44]. In addition, PARP-1 activation is associated with inflammation, indicating that targeting PARP is a valuable therapeutic strategy for inflammatory disorders, and some inhibitors are in clinical trials [45]. "
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