Regulation of Poly(A)-specific ribonuclease Activity by Reversible Lysine Acetylation
Open AccessPoly(A)-specific ribonuclease (PARN) is an RNA processing enzyme that regulates biological processes, such as telomere maintenance, through its enzymatic activity. PARN is a 3’ exoribonuclease that cleaves RNA bases at the 3’ end, one nucleotide at a time. PARN has the highest substrate affinity for adenosines, conferring it the title of a deadenylase; however, PARN is also efficient at cleaving other bases. PARN’s deadenylase activity allows it to remove poly(A) tails at the 3’ end of both coding and non-coding RNAs. PARN’s deadenylation of cytoplasmic messenger RNAs (mRNAs), for example TP53 mRNA, has a destabilizing effect. However, PARN’s deadenylation of non-coding RNAs has been shown to promote their stability. PARN also mediates the maturation of non-coding RNAs by cleaving excess adenosine and non-adenosine bases at the 3’ end, enabling non-coding RNAs to carry out their functions. PARN can regulate the stability and maturation of a variety of non-coding RNAs such as: microRNAs (miRNAs), Y RNAs, small cajal body RNAs (scaRNAs), small nucleolar RNAs (snoRNAs), the 18S ribosomal RNA (rRNA) and the human telomerase RNA component (hTR).Recent studies have highlighted PARN’s role in regulating the maturation of the human telomerase RNA component (hTR), a non-coding RNA required for telomere elongation. Specifically, PARN cleaves the 3’ end of immature, polyadenylated hTR to form the mature, non-polyadenylated template. Mature hTR can then be used as a template by the human telomerase reverse transcriptase (TERT) to extend telomeres.Despite PARN’s critical role in mediating telomere maintenance, little is known about how PARN’s function is regulated by post-translational modifications (PTMs). To date, all that is known is PARN is phosphorylated at serine 557, which alters its protein interactions. In this study, we examined whether PARN is modified by another PTM, acetylation, and what effect acetylation has on PARN’s activity. We found PARN can be acetylated by the acetyltransferases MOF and PCAF but is primarily acetylated by p300 at lysine 566. Furthermore, we discovered PARN is primarily deacetylated by sirtuin1 (SIRT1), although SIRT2, SIRT3, SIRT4, SIRT6 and SIRT7 also reduced PARN’s acetylation to a lesser degree. We also uncovered how acetylation of PARN can decrease its enzymatic activity both in vitro, using a synthetic RNA probe, and in vivo, by quantifying endogenous levels of adenylated hTR. Furthermore, we found SIRT1 can regulate levels of adenylated hTR through PARN. Interestingly, we also discovered SIRT1 can regulate the adenylation of PARN’s snoRNA and scaRNA targets. Overall, our study reveals a new mechanism by which acetylation and deacetylation of PARN can regulate its enzymatic activity and the maturation of its RNA target hTR. Thus, PARN’s acetylation status might play a larger role in regulating telomere length.
- All rights reserved
Notice to Authors
If you are the author of this work and you have any questions about the information on this page, please use the Contact form to get in touch with us.