期刊
CELLS
卷 11, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/cells11030521
关键词
genome stability; cancer; mismatch repair; mammalian deadenylase; mRNA degradation; gene regulation
类别
资金
- Nordea-fonden, Olav Thon Foundation
- Sven Wewers fond
- Novo Nordisk Foundation [NNF17OC0027812]
- China Scholarship Council, China - Chinese National Natural Science Foundation [31800682]
- Copenhagen Center for Glycomics
- Danish National Research Foundation [DNRF107]
DNA mismatch repair (MMR) is an important DNA repair pathway that, when defective, is linked to carcinogenesis and drug resistance. This study demonstrates that depletion of CNOT6, which is overexpressed in cancer cells, sensitizes cells to DNA damage and enhances apoptosis. Depletion of CNOT6 also upregulates MMR and decreases mutation frequency, possibly through stabilizing mRNA transcripts from MMR genes and increasing MMR protein expression.
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.
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