Research ArticleCardiovascular Biology

The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function

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Science Signaling  06 Feb 2018:
Vol. 11, Issue 516, eaan3638
DOI: 10.1126/scisignal.aan3638

Protecting the heart by destabilizing mRNA

The removal of polyadenylate tails from mRNAs by the CCR4-NOT complex marks these mRNAs for degradation. Yamaguchi et al. (see also the Focus by Das) found that this activity of this complex was required to prevent cell death in the heart. Mice deficient in a component of this complex suffered from cardiac dysfunction and died of heart failure due to cardiomyocyte death. The CCR4-NOT complex deadenylated Atg7 mRNA, which encodes a protein required for autophagy, a process by which cellular constituents and organelles are digested. The increase in Atg7 in the mutant mice resulted in activation of cell death–associated genes by the transcription factor p53. Drugs that increase autophagy have been explored for the treatment of various diseases, but the authors note that their results raise the possibility of cardiovascular side effects for such drugs.


Shortening and removal of the polyadenylate [poly(A)] tail of mRNA, a process called deadenylation, is a key step in mRNA decay that is mediated through the CCR4-NOT (carbon catabolite repression 4–negative on TATA-less) complex. In our investigation of the regulation of mRNA deadenylation in the heart, we found that this complex was required to prevent cell death. Conditional deletion of the CCR4-NOT complex components Cnot1 or Cnot3 resulted in the formation of autophagic vacuoles and cardiomyocyte death, leading to lethal heart failure accompanied by long QT intervals. Cnot3 bound to and shortened the poly(A) tail of the mRNA encoding the key autophagy regulator Atg7. In Cnot3-depleted hearts, Atg7 expression was posttranscriptionally increased. Genetic ablation of Atg7, but not Atg5, increased survival and partially restored cardiac function of Cnot1 or Cnot3 knockout mice. We further showed that in Cnot3-depleted hearts, Atg7 interacted with p53 and modulated p53 activity to induce the expression of genes encoding cell death–promoting factors in cardiomyocytes, indicating that defects in deadenylation in the heart aberrantly activated Atg7 and p53 to promote cell death. Thus, mRNA deadenylation mediated by the CCR4-NOT complex is crucial to prevent Atg7-induced cell death and heart failure, suggesting a role for mRNA deadenylation in targeting autophagy genes to maintain normal cardiac homeostasis.

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