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The Wonders of Flap Endonucleases: Structure, Function, Mechanism and Regulation

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The Eukaryotic Replisome: a Guide to Protein Structure and Function

Part of the book series: Subcellular Biochemistry ((SCBI,volume 62))

Abstract

Processing of Okazaki fragments to complete lagging strand DNA synthesis requires coordination among several proteins. RNA primers and DNA synthesised by DNA polymerase α are displaced by DNA polymerase δ to create bifurcated nucleic acid structures known as 5′-flaps. These 5′-flaps are removed by Flap Endonuclease 1 (FEN), a structure-specific nuclease whose divalent metal ion-dependent phosphodiesterase activity cleaves 5′-flaps with exquisite specificity. FENs are paradigms for the 5′ nuclease superfamily, whose members perform a wide variety of roles in nucleic acid metabolism using a similar nuclease core domain that displays common biochemical properties and structural features. A detailed review of FEN structure is undertaken to show how DNA substrate recognition occurs and how FEN achieves cleavage at a single phosphate diester. A proposed double nucleotide unpairing trap (DoNUT) is discussed with regards to FEN and has relevance to the wider 5′ nuclease superfamily. The homotrimeric proliferating cell nuclear antigen protein (PCNA) coordinates the actions of DNA polymerase, FEN and DNA ligase by facilitating the hand-off intermediates between each protein during Okazaki fragment maturation to maximise through-put and minimise consequences of intermediates being released into the wider cellular environment. FEN has numerous partner proteins that modulate and control its action during DNA replication and is also controlled by several post-translational modification events, all acting in concert to maintain precise and appropriate cleavage of Okazaki fragment intermediates during DNA replication.

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Acknowledgements

This article was supported by the European Union 7th Research Framework Programme (FP7)-Marie Curie International Incoming Fellowship Project No. 254386 (LDF), National Cancer Institute grants RO1CA081967, P01 CA092584 (JAT), BBSRC grant BBF0147321 (JAG), and RO1CA073764 (BS).

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Authors and Affiliations

  1. Department of Chemistry, Centre for Chemical Biology, Krebs Institute, University of Sheffield, Sheffield, S3 7HF, UK

    L. David Finger, John M. Atack & Jane Grasby

  2. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA

    Susan Tsutakawa & John Tainer

  3. Physical Biosciences Division, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Scott Classen

  4. Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA

    John Tainer

  5. Skaggs Institute for Chemical Biology, La Jolla, CA, 92037, USA

    John Tainer

  6. Division of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, 91010, USA

    Binghui Shen

  7. College of Life Sciences, Zhejiang University, Hangzhou, 310058, China

    Binghui Shen

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  1. L. David Finger
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Correspondence to L. David Finger .

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  1. , School of Biology, University of St Andrews, Biomedical Sciences Research Complex, North Haugh, St Andrews, KY16 9ST, Fife, United Kingdom

    Stuart MacNeill

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Finger, L.D. et al. (2012). The Wonders of Flap Endonucleases: Structure, Function, Mechanism and Regulation. In: MacNeill, S. (eds) The Eukaryotic Replisome: a Guide to Protein Structure and Function. Subcellular Biochemistry, vol 62. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4572-8_16

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