CNOT6

CNOT6 Full Name

CCR4-NOT transcription complex, subunit 6

CNOT6 Introduction

CCR4-NOT transcription complex subunit 6 (CNOT6), also known as CCR4a, is one of the two catalytic deadenylase subunits of the CCR4-NOT complex, the predominant cytoplasmic mRNA deadenylase in eukaryotic cells. Encoded by the CNOT6 gene on chromosome 5q35.3, CNOT6 belongs to the DEDD (Asp-Glu-Asp-Asp) superfamily of exonucleases and functions as a 3'-to-5' exoribonuclease that specifically removes the poly(A) tail from mRNA molecules. Deadenylation is the rate-limiting and often initiating step in the major mRNA decay pathways, positioning CNOT6 as a critical gatekeeper of mRNA stability and turnover.

Figure 1. The role of cnot6 in mrna degradation and gene regulation.

Catalytic Mechanism and Substrate Specificity
CNOT6 harbors a conserved exonuclease-endonuclease-phosphatase (EEP) domain that coordinates two magnesium ions essential for phosphodiester bond hydrolysis. Its 3'-to-5' exonuclease activity progressively shortens mRNA poly(A) tails, with a preference for poly(A) substrates over other homopolymeric sequences. CNOT6 and its paralog CNOT6L (CCR4b) exhibit partially overlapping but non-redundant substrate specificities, enabling the CCR4-NOT complex to regulate distinct subsets of cellular transcripts. The catalytic activity of CNOT6 is modulated by its association with the CNOT1 scaffold and interactions with RNA-binding proteins such as tristetraprolin (TTP) and Pumilio, which recruit CNOT6-containing complexes to specific mRNAs harboring AU-rich elements (AREs) or Pumilio response elements (PREs) in their 3' untranslated regions.

CNOT6 in Immune Regulation, Inflammation, and Cancer
CNOT6 plays a pivotal role in the post-transcriptional regulation of inflammatory and immune response genes. Through its recruitment by TTP, CNOT6 mediates the rapid deadenylation and degradation of mRNAs encoding pro-inflammatory cytokines including TNF-α, IL-6, and GM-CSF, serving as a critical brake on excessive inflammation. Mice deficient in CNOT6 exhibit heightened inflammatory responses and increased susceptibility to LPS-induced septic shock. In cancer, CNOT6 dysregulation has been implicated in tumorigenesis: in acute lymphoblastic leukemia, CNOT6 functions as a tumor suppressor by targeting oncogenic transcripts (such as c-Myc) for degradation, while in other tumor types CNOT6-mediated silencing of tumor suppressor mRNAs may promote malignant progression. These context-dependent roles highlight the therapeutic potential of modulating CNOT6 activity in both inflammatory and malignant diseases.

Alternate Names for CNOT6

CNOT6; CCR4-NOT transcription complex, subunit 6; CCR4-NOT transcription complex subunit 6; CCR4; KIAA1194; cytoplasmic deadenylase; carbon catabolite repression 4 protein; carbon catabolite repressor protein 4 homolog;