Flap endonuclease 1 and its role in eukaryotic DNA metabolism

Nazarkina, Zh. K.; Lavrik, Olga I.; Ходырева, С. Н.

doi:10.1134/s0026893308030035

Cited by 10 publications

(10 citation statements)

References 93 publications

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“…16.1b–i) (Nazarkina et al 2008; Shen et al 2005). The divalent metal ion-dependent phosphodiesterase activity of FENs exclusively generates 5′-phosphate monoester and 3′-hydroxyl products (Pickering et al 1999).…”

Section: 2 Biochemical Activitymentioning

confidence: 99%

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

Finger

Atack

Tsutakawa

et al. 2012

Subcellular Biochemistry

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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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Section: 2 Biochemical Activitymentioning

confidence: 99%

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

Finger

Atack

Tsutakawa

et al. 2012

Subcellular Biochemistry

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“…Details of the role of FEN1 in these two classical pathways were previously reviewed (1,4,38,39). It should be noted that the mechanisms of RNA primer removal in human and yeast are likely different.…”

Section: Multiple Structure-specific Nuclease Activities and Their Bimentioning

confidence: 99%

Functional regulation of FEN1 nuclease and its link to cancer

Zheng

Jia

Finger

et al. 2010

Nucleic Acids Research

185

194

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Flap endonuclease-1 (FEN1) is a member of the Rad2 structure-specific nuclease family. FEN1 possesses FEN, 5′-exonuclease and gap-endonuclease activities. The multiple nuclease activities of FEN1 allow it to participate in numerous DNA metabolic pathways, including Okazaki fragment maturation, stalled replication fork rescue, telomere maintenance, long-patch base excision repair and apoptotic DNA fragmentation. Here, we summarize the distinct roles of the different nuclease activities of FEN1 in these pathways. Recent biochemical and genetic studies indicate that FEN1 interacts with more than 30 proteins and undergoes post-translational modifications. We discuss how FEN1 is regulated via these mechanisms. Moreover, FEN1 interacts with five distinct groups of DNA metabolic proteins, allowing the nuclease to be recruited to a specific DNA metabolic complex, such as the DNA replication machinery for RNA primer removal or the DNA degradosome for apoptotic DNA fragmentation. Some FEN1 interaction partners also stimulate FEN1 nuclease activities to further ensure efficient action in processing of different DNA structures. Post-translational modifications, on the other hand, may be critical to regulate protein–protein interactions and cellular localizations of FEN1. Lastly, we also review the biological significance of FEN1 as a tumor suppressor, with an emphasis on studies of human mutations and mouse models.

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“…Its involvement in multiple protein-protein interactions makes it a central player in various DNA metabolic pathways [42]. Our findings on the association between FEN1 and telomerase have prompted us to further analyze this association.…”

Section: Discussionmentioning

confidence: 99%

Mapping the FEN1 interaction domain with hTERT

Sampathi

Chai

2011

Biochemical and Biophysical Research Communications

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The activity of telomerase in cancer cells is tightly regulated by numerous proteins including DNA replication factors. However, it is unclear how replication proteins regulate telomerase action in higher eukaryotic cells. Previously we have demonstrated that the multifunctional DNA replication and repair protein flap endonuclease 1 (FEN1) is in complex with telomerase and may regulate telomerase activity in mammalian cells. In this study, we further analyzed the nature of this association. Our results show that FEN1 and telomerase association occurs throughout the S phase, with the maximum association in the mid S phase. We further mapped the physical domains in FEN1 required for this association and found that the C terminus and the nuclease domain of FEN1 are involved in this interaction, whereas the PCNA binding ability of FEN1 is dispensable for the interaction. These results provide insights into the nature of possible proteinprotein associations that telomerase participates in for maintaining functional telomeres.

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Flap endonuclease 1 and its role in eukaryotic DNA metabolism

Cited by 10 publications

References 93 publications

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

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

Functional regulation of FEN1 nuclease and its link to cancer

Mapping the FEN1 interaction domain with hTERT

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