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The DNA repair protein, O(6)-methylguanine-DNA methyltransferase is a proteolytic target for the E6 human papillomavirus oncoprotein.

Publication ,  Journal Article
Srivenugopal, KS; Ali-Osman, F
Published in: Oncogene
August 29, 2002

We have previously shown that O(6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein that protects tissues against toxic and carcinogenic effects of alkylating agents, is degraded through ubiquitination-dependent proteolysis. Here, we investigated the role of the human papillomavirus (HPV) E6 protein in MGMT degradation. In three pairs of isogenic human tumor cell lines in which a member of each pair expressed the E6 protein through stable transfection (HCT116/HCT116-E6, MCF7/MCF7-E6, and RKO/RKO-E6), we found a consistent 40-55% reduction in the MGMT protein level and its activity in all E6-expressing cells compared with the parent cells (P=<0.05). E6 expression did not, however, alter the levels of MGMT mRNA. Addition of the recombinant MGMT (rMGMT) protein to extracts of HCT116/E6 cells resulted in the binding of E6 to MGMT. Further, the purified E6 protein promoted the degradation of rMGMT in rabbit reticulocyte lysates. Immunoprecipitation assays showed the presence of a ternary protein complex between MGMT, E6, and the cellular ubiquitin-ligase E6-associated protein (E6-AP). Transient transfection of the p53-null H1299 lung tumor cells with an E6 construct also down-regulated the MGMT. The MGMT protein also showed structural features that are compatible for interaction with the E6, and E6-AP components. Collectively, these data suggest that the oncogenic E6 proteins enhance the ubiquitin-dependent proteolysis of MGMT.

Duke Scholars

Published In

Oncogene

DOI

ISSN

0950-9232

Publication Date

August 29, 2002

Volume

21

Issue

38

Start / End Page

5940 / 5945

Location

England

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Ubiquitin
  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Repressor Proteins
  • Rabbits
  • Oncology & Carcinogenesis
  • Oncogene Proteins, Viral
  • O(6)-Methylguanine-DNA Methyltransferase
  • Magnesium
 

Citation

APA
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ICMJE
MLA
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Srivenugopal, K. S., & Ali-Osman, F. (2002). The DNA repair protein, O(6)-methylguanine-DNA methyltransferase is a proteolytic target for the E6 human papillomavirus oncoprotein. Oncogene, 21(38), 5940–5945. https://doi.org/10.1038/sj.onc.1205762
Srivenugopal, Kalkunte S., and Francis Ali-Osman. “The DNA repair protein, O(6)-methylguanine-DNA methyltransferase is a proteolytic target for the E6 human papillomavirus oncoprotein.Oncogene 21, no. 38 (August 29, 2002): 5940–45. https://doi.org/10.1038/sj.onc.1205762.
Srivenugopal, Kalkunte S., and Francis Ali-Osman. “The DNA repair protein, O(6)-methylguanine-DNA methyltransferase is a proteolytic target for the E6 human papillomavirus oncoprotein.Oncogene, vol. 21, no. 38, Aug. 2002, pp. 5940–45. Pubmed, doi:10.1038/sj.onc.1205762.

Published In

Oncogene

DOI

ISSN

0950-9232

Publication Date

August 29, 2002

Volume

21

Issue

38

Start / End Page

5940 / 5945

Location

England

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Ubiquitin
  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Repressor Proteins
  • Rabbits
  • Oncology & Carcinogenesis
  • Oncogene Proteins, Viral
  • O(6)-Methylguanine-DNA Methyltransferase
  • Magnesium