CNOT6: A Novel Regulator of DNA Mismatch Repair
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CNOT6 : A Novel Regulator of DNA Mismatch Repair. / 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.
In: Cells, Vol. 11, No. 3, 521, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - CNOT6
T2 - A Novel Regulator of DNA Mismatch Repair
AU - Song, Peng
AU - Liu, Shaojun
AU - Liu, Dekang
AU - Keijzers, Guido
AU - Bakula, Daniela
AU - Duan, Shunlei
AU - de Wind, Niels
AU - Ye, Zilu
AU - Vakhrushev, Sergey Y.
AU - Scheibye-Knudsen, Morten
AU - Rasmussen, Lene Juel
N1 - Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Cancer
KW - Gene regulation
KW - Genome stability
KW - Mammalian deadenylase
KW - Mismatch repair
KW - MRNA degradation
U2 - 10.3390/cells11030521
DO - 10.3390/cells11030521
M3 - Journal article
C2 - 35159331
AN - SCOPUS:85123751578
VL - 11
JO - Cells
JF - Cells
SN - 2073-4409
IS - 3
M1 - 521
ER -
ID: 291600982