Mixed tailing by TENT4A and TENT4B shields mRNA from rapid deadenylation

Abstract

RNA tails play integral roles in the regulation of messenger RNA (mRNA) translation and decay. Guanylation of the poly(A) tail was discovered recently, yet the enzymology and function remain obscure. Here we identify TENT4A (PAPD7) and TENT4B (PAPD5) as the enzymes responsible for mRNA guanylation. Purified TENT4 proteins generate a mixed poly(A) tail with intermittent non-adenosine residues, the most common of which is guanosine. A single guanosine residue is sufficient to impede the deadenylase CCR4-NOT complex, which trims the tail and exposes guanosine at the 3' end. Consistently, depletion of TENT4A and TENT4B leads to a decrease in mRNA half-life and abundance in cells. Thus, TENT4A and TENT4B produce a mixed tail that shields mRNA from rapid deadenylation. Our study unveils the role of mixed tailing and expands the complexity of posttranscriptional gene regulation.

PAPD5/7 Are Host Factors That Are Required for Hepatitis B Virus RNA Stabilization

“…Second, oligonucleotide‐mediated knockdown of individual TRAMP‐like complex components had no significant effect on HBV RNA levels. These data are in line with a new report suggesting that PAPD5 and PAPD7 regulate mRNA stability in a TRAMP‐independent manner …”

“…These studies may explain why RG7834 activity is sensitive to deletion of HBV HPRE element, which is also located upstream of the poly(A) signal . Furthermore, a recent report suggested that PAPD5 and PAPD7 are responsible for guanylation of the poly(A) tail that shields mRNA from rapid deadenylation . It was noted that mRNA transcripts encoding secreted proteins are frequently guanylated and are more sensitive to PAPD5 and PAPD7 depletion.…”

Connections between 3′ end processing and DNA damage response: Ten years later

“…These studies suggest that mRNA decay is important for making sure the death program passes the “point of no return.” In non‐apoptotic cells, this pathway of TUTases and DIS3L2 act in quality control pathways of mRNAs and ncRNAs (Pirouz, Du, Munafò, & Gregory, ; Ustianenko et al, ). In contrast to the destabilizing effect of terminal uridyl, a more recent report has identified promiscuous nucleotidyl transferase activity leading to guanylation of the poly(A) tail that protects mRNAs from degradation (Chang et al, ; Y. Lim et al, ). TENT4A (PAPD7) and TENT4B (PAPD5) are noncanonical poly(A) polymerases with terminal nucleotidyltransferase activity that catalyze preferentially the transfer of ATP and GTP on mRNA 3′ poly(A) tail (Y. Lim et al, ).…”

“…In contrast to the destabilizing effect of terminal uridyl, a more recent report has identified promiscuous nucleotidyl transferase activity leading to guanylation of the poly(A) tail that protects mRNAs from degradation (Chang et al, ; Y. Lim et al, ). TENT4A (PAPD7) and TENT4B (PAPD5) are noncanonical poly(A) polymerases with terminal nucleotidyltransferase activity that catalyze preferentially the transfer of ATP and GTP on mRNA 3′ poly(A) tail (Y. Lim et al, ). Importantly, a single guanosine residue is sufficient to impede the mRNA decay‐mediated by deadenylase CCR4‐NOT complex.…”

“…TENT4A (PAPD7) and TENT4B (PAPD5) are noncanonical poly(A) polymerases with terminal nucleotidyltransferase activity that catalyze preferentially the transfer of ATP and GTP on mRNA 3 0 poly(A) tail (Y. Lim et al, 2018). Importantly, a single guanosine residue is sufficient to impede the mRNA decay-mediated by deadenylase CCR4-NOT complex.…”