Human AP endonuclease suppresses DNA mismatch repair activity leading to microsatellite instability.
The multifunctional mammalian apurinic/apyrimidinic (AP) endonuclease (APE) participates in the repair of AP sites in the cellular DNA as well as participating in the redox regulation of the transcription factor function. The function of APE is considered as the rate-limiting step in DNA base excision repair. Paradoxically, an unbalanced increase in APE protein leads to genetic instability. Therefore, we investigated the mechanisms of genetic instability that are induced by APE. Here, we report that the overexpression of APE protein disrupts the repair of DNA mismatches, which results in microsatellite instability (MSI). We found that expression of APE protein led to the suppression of the repair of DNA mismatches in the normal human fibroblast cells. Western blot analysis revealed that hMSH6 protein was markedly reduced in the APE-expressing cells. Moreover, the addition of purified Mutalpha (MSH2 and MSH6 complex) to the extracts from the APE-expressing cells led to the restoration of mismatch repair (MMR) activity. By performing MMR activity assay and MSI analysis, we found that the co-expression of hMSH6 and APE exhibited the microsatellite stability, whereas the expression of APE alone generated the MSI-high phenotype. The APE-mediated decrease in MMR activity described here demonstrates the presence of a new and highly effective APE-mediated mechanism for MSI.
Chang
In-Youb
IY
Research Center for Proteinous Materials, Chosun University, 375 Seusuk-dong, Gwangju 501-759, Korea.
Kim
Soo-Hyun
SH
Cho
Hyun-Ju
HJ
Lee
Do Young
DY
Kim
Mi-Hwa
MH
Chung
Myung-Hee
MH
You
Ho Jin
HJ
D020137:Base Pair Mismatch; D002460:Cell Line; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D018895:Microsatellite Repeats; D051718:MutS Homolog 2 Protein; D011518:Proto-Oncogene Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase