Adenomatous polyposis coli interacts with flap endonuclease 1 to block its nuclear entry and function.
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 (Lys(365)Lys(366)Lys(367)), 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.
Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, FL 32610, USA.
Aruna S
AS
Jaiswal
Melissa L
ML
Armas
Tadahide
T
Izumi
Phyllis R
PR
Strauss
Satya
S
Narayan
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D002384:Catalysis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004260:DNA Repair; D045585:Flap Endonucleases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D019913:Nuclear Localization Signals / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D025941:Protein Interaction Mapping
D025601:Adenomatous Polyposis Coli Protein; D019913:Nuclear Localization Signals; D045585:Flap Endonucleases