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Identification of a novel, widespread, and functionally important PCNA-binding motif

Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway

Correspondence to Marit Otterlei: marit.otterlei{at}ntnu.no

Numerous proteins, many essential for the DNA replication machinery, interact with proliferating cell nuclear antigen (PCNA) through the PCNA-interacting peptide (PIP) sequence called the PIP box. We have previously shown that the oxidative demethylase human AlkB homologue 2 (hABH2) colocalizes with PCNA in replication foci. In this study, we show that hABH2 interacts with a posttranslationally modified PCNA via a novel PCNA-interacting motif, which we term AlkB homologue 2 PCNA-interacting motif (APIM). We identify APIM in >200 other proteins involved in DNA maintenance, transcription, and cell cycle regulation, and verify a functional APIM in five of these. Expression of an APIM peptide increases the cellular sensitivity to several cytostatic agents not accounted for by perturbing only the hABH2–PCNA interaction. Thus, APIM is likely to mediate PCNA binding in many proteins involved in DNA repair and cell cycle control during genotoxic stress.

Abbreviations used in this paper: APIM, AlkB homologue 2 PCNA-interacting motif; BER, base excision repair; FRET, fluorescence resonance energy transfer; hABH2, human AlkB homologue 2; HcRed, Hereactis crispa RFP; IP, immunoprecipitation; LC, liquid chromatography; MMC, mitomycin C; MMS, methyl methanesulfonate; MS, mass spectrometry; PCNA, proliferating cell nuclear antigen; PCV, packed cell volume; pI, isoelectric point; PIP, PCNA-interacting peptide; PTM, posttranslational modification; TMZ, temozolomide; Topo, topoisomerase; WB, Western blot; WT, wild type.

© 2009 Gilljam et al.
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