This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, D. Articles by Lopez, C. D. Search for Related Content PubMed PubMed Citation Articles by Chen, D. Articles by Lopez, C. D.

The p53 Pathway Promotes Efficient Mitochondrial DNA Base Excision Repair in Colorectal Cancer Cells

¹ Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon and ² Shandong Tumor Hospital and Institute, Jinan, China

Requests for reprints: Charles D. Lopez, Department of Medicine, Division of Hematology and Medical Oncology, Mail Code L586B, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97201-3098. Phone: 503-494-8321; Fax: 503-418-0844; E-mail: lopezc{at}ohsu.edu.

The tumor suppressor p53 plays a central role in the DNA damage response. p53 enhances base excision repair (BER), in part, through direct interaction with the repair complex. Mitochondrial DNA (mtDNA) is repaired by a mtBER pathway. Many colorectal cancers harbor mtDNA mutations that are associated with poor prognosis. In addition to modulating the apoptotic response, mitochondria-localized p53 also stimulates mtBER. However, the mechanisms by which p53 enhances colorectal cancer mtBER after stress remain unclear. To explore this, we used colorectal cancer cells isogenic for p53 (HCT116p53+/+ and HCT116p53–/–). p53+/+ cells more efficiently repaired H₂O₂ damaged DNA in vivo as measured by semiquantitative mtDNA displacement loop PCR. Mitochondrial extracts from p53+/+ cells more efficiently stimulated ³²P-dCTP incorporation into a uracil-oligonucleotide. Recombinant p53 complemented p53–/– mitochondrial extract repair of uracil or 8-oxo-G–containing oligonucleotides. As a measure of DNA glycosylase activity, p53+/+ mitochondrial extracts more efficiently incised uracil or 8-oxo-G oligonucleotides, although recombinant p53 could not stimulate oligonucleotide incision. p53 did not influence mitochondrial apurinic/apyrimidinic endonuclease activity measured by incision of a tetrahydrofuran-oligonucleotide. p53+/+ mitochondrial extracts had higher DNA polymerase- activity measured by ³²P-dCTP incorporation into a single-nucleotide gap oligonucleotide, and recombinant p53 complemented p53–/– mitochondrial extract DNA polymerase- activity. mtDNA ligase activity was not affected by p53 status. p53 protein was detected in an inner mitochondrial membrane subfraction containing components of the mtBER complex. Our data suggest that an intact p53 pathway stimulates specific mtBER steps and provides mechanistic insight into the development of mtDNA mutations in colorectal cancer. (Cancer Res 2006; 66(7): 3485-94)

This article has been cited by other articles:

				G. S. Shadel Expression and Maintenance of Mitochondrial DNA: New Insights into Human Disease Pathology Am. J. Pathol., June 1, 2008; 172(6): 1445 - 1456. [Abstract] [Full Text] [PDF]

				V. Tembe and B. R. Henderson BARD1 Translocation to Mitochondria Correlates with Bax Oligomerization, Loss of Mitochondrial Membrane Potential, and Apoptosis J. Biol. Chem., July 13, 2007; 282(28): 20513 - 20522. [Abstract] [Full Text] [PDF]

				R. Nithipongvanitch, W. Ittarat, J. M. Velez, R. Zhao, D. K. St. Clair, and T. D. Oberley Evidence for p53 as Guardian of the Cardiomyocyte Mitochondrial Genome Following Acute Adriamycin Treatment J. Histochem. Cytochem., June 1, 2007; 55(6): 629 - 639. [Abstract] [Full Text] [PDF]

				S. Zhou, S. Kachhap, W. Sun, G. Wu, A. Chuang, L. Poeta, L. Grumbine, S. K. Mithani, A. Chatterjee, W. Koch, et al. Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck PNAS, May 1, 2007; 104(18): 7540 - 7545. [Abstract] [Full Text] [PDF]