CNOT6: A Novel Regulator of DNA Mismatch Repair

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 3; p. 521
• Main Authors: Song, Peng, Liu, Shaojun, Liu, Dekang, Keijzers, Guido, Bakula, Daniela, Duan, Shunlei, de Wind, Niels, Ye, Zilu, Vakhrushev, Sergey Y, Scheibye-Knudsen, Morten, Rasmussen, Lene Juel
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 02.02.2022; MDPI
• Subjects: Acute lymphoblastic leukemia; Acute myeloid leukemia; Antibodies; Apoptosis; Apoptosis - genetics; cancer; Carcinogenesis; Colorectal cancer; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Mismatch Repair - genetics; DNA repair; DNA Replication; Drug resistance; Gene deletion; gene regulation; genome stability; Genomes; Humans; Insertion; Leukemia; Lymphatic leukemia; Male; mammalian deadenylase; Mismatch repair; mRNA degradation; mRNA stability; Mutation; Plasmids; Polyadenine; Prostate cancer; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tumorigenesis; Yeast; United States > US; Switzerland; New Jersey; Germany; genome stability; mismatch repair; mRNA degradation; cancer; gene regulation; mammalian deadenylase
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11030521

DNA mismatch repair (MMR) is a highly conserved pathway that corrects both base-base mispairs and insertion-deletion loops (IDLs) generated during DNA replication. Defects in MMR have been linked to carcinogenesis and drug resistance. However, the regulation of MMR is poorly understood. Interestingly, CNOT6 is one of four deadenylase subunits in the conserved CCR4-NOT complex and it targets poly(A) tails of mRNAs for degradation. CNOT6 is overexpressed in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and androgen-independent prostate cancer cells, which suggests that an altered expression of CNOT6 may play a role in tumorigenesis. Here, we report that a depletion of CNOT6 sensitizes human U2OS cells to N-methyl-N'nitro-N-nitrosoguanidine (MNNG) and leads to enhanced apoptosis. We also demonstrate that the depletion of CNOT6 upregulates MMR and decreases the mutation frequency in MMR-proficient cells. Furthermore, the depletion of CNOT6 increases the stability of mRNA transcripts from MMR genes, leading to the increased expression of MMR proteins. Our work provides insight into a novel CNOT6-dependent mechanism for regulating MMR.