In previous studies, we found that adenomatous polyposis coli (APC) blocks the base excision repair (BER) pathway by interacting with 5′-flap endonuclease 1 (Fen1). In this study, we identify the molecular features that contribute to the formation and/or stabilization of the APC/Fen1 complex that determines the extent of BER inhibition, and the subsequent accumulation of DNA damage creates mutagenic lesions leading to transformation susceptibility. We show here that APC binds to the nuclear localization sequence of Fen1 (Lys365Lys366Lys367), which prevents entry of Fen1 into the nucleus and participation in Pol-β-directed long-patch BER. We also show that levels of the APC/Fen1 complex are higher in breast tumors than in the surrounding normal tissues. These studies demonstrate a novel role for APC in the suppression of Fen1 activity in the BER pathway and a new biomarker profile to be explored to identify individuals who may be susceptible to the development of mammary and other tumors.
|Number of pages||14|
|Journal||Neoplasia (United States)|
|State||Published - Jun 2012|
Bibliographical noteFunding Information:
Abbreviations: APC, adenomatous polyposis coli; DRI domain, DNA repair inhibitory domain; Fen1, flap endonuclease 1; LP-BER, long-patch base excision repair; NLS, nuclear localization signal; Pol-β, DNA polymerase β Address all correspondence to: Satya Narayan, PhD, Department of Anatomy and Cell Biology, Basic Science Bldg, Room B1-016, PO Box 100235, University of Florida, Gainesville, FL 32610. E-mail: email@example.com 1Financial support for these studies was provided by grants from the National Institutes of Health (R01-CA097031 and R01-CA100247 to S.N. and RO1-CA98664 to T.I.) and Flight Attendant Medical Research Institute, Miami, FL (CIA-072088) to S.N. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. 2These authors equally contributed to this study. Received 12 April 2012; Revised 4 May 2012; Accepted 7 May 2012 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1593/neo.12680
ASJC Scopus subject areas
- Cancer Research