Abstract
Human exonuclease 1 (hEXO1) has been implicated in DNA mismatch repair (MMR), replication, and recombination, but the nature of its interaction with these cellular processes is still ambiguous. We show that hEXO1 colocalizes with proliferating cell nuclear antigen (PCNA) at DNA replication sites and that the C-terminal region of hEXO1 is sufficient for this localization. We also show that both hMLH1–hPMS2 (MutLα) and hMLH1–hEXO1 complexes are formed in a reaction mixture containing all three proteins. Moreover, hEXO1 5′ double-stranded exonuclease activity on a homoduplex substrate but not on a substrate containing a G/T mismatch was inhibited by complex formation with hMSH2–hMSH6 (MutSα) or MutLα. Taken together, the results support a model in which hEXO1 plays a role in events at the replication sites as well as a functional role in the MMR and/or recombination processes.
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Acknowledgements
We are grateful to Anne Marie Bundgaard, Gerda Olesen, Lene Markussen, Bente Rotbøl, and Joan Christiansen for expert technical assistance. We are grateful to Dr Jochen Genschel and Dr Poul Modrich for the generous gift of antibodies against hEXO1 and to Dr David M Wilson III and Dr Christina Cardoso for plasmids. We are also grateful to Drs Niels de Wind and Andrew Buermeyer for murine cell lines. The Danish Cancer Society (LJR), Danish Research Council (LJR), Villum Kann Rasmussen Foundation (ACJ), the NOVO-Nordisk foundation (FCN), and the John and Birthe Meier Foundation (FCN) supported this work.
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Nielsen, F., Jäger, A., Lützen, A. et al. Characterization of human exonuclease 1 in complex with mismatch repair proteins, subcellular localization and association with PCNA. Oncogene 23, 1457–1468 (2004). https://doi.org/10.1038/sj.onc.1207265
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DOI: https://doi.org/10.1038/sj.onc.1207265
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