Functional regulation of FEN1 nuclease and its link to cancer

Abstract

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.

Overexpression of androgen receptor enhances the binding of the receptor to the chromatin in prostate cancer

“…FEN1 encodes a structure-specific metallonuclease that interacts with several other proteins involved in DNA replication, apoptosis, DNA repair and telomere stability (Zheng et al, 2010). Somatic mutations of FEN1 have been reported in several common cancers (Zheng et al, 2007).…”

Flap endonuclease 1 polymorphisms (rs174538 and rs4246215) contribute to an increased cancer risk: Evidence from a meta-analysis

“…Flap endonuclease 1 (FEN1) is a versatile, structure specific and multifunctional nuclease involved in DNA replication and repair (1,2). Human FEN1, which is the archetypal member of the Rad2 nuclease family (3,4), is located on chromosome 11q12 and consists of two exons and one intron.…”

“…Furthermore, FEN1 can be stimulated to promote apoptotic DNA fragmentation following apoptotic stimuli, acting as a 5' exonuclease (1) and a gap-dependent endonuclease (7,8), as reported via its ability to participate in multiple protein-protein interactions. Thus far, >30 FEN1-interacting proteins have been identified (2). Of these FEN1 interaction partners, proliferating cell nuclear antigen (PCNA), which was initially identified as a replication accessory protein, accompanies FEN1 in all FEN1-involved DNA metabolic pathways except for the apoptotic DNA fragmentation pathway, suggesting a critical role of the FEN1/PCNA interaction in regulating LP-BER (9).…”

Repair complexes of FEN1 endonuclease, DNA, and Rad9-Hus1-Rad1 are distinguished from their PCNA counterparts by functionally important stability

“…By removing the 5′ ssDNA or RNA flap from such substrates, FEN1 produces a single nicked product that could be sealed by the subsequent action of a DNA ligase (4). Consistent with its crucial role in DNA replication and repair, FEN1 is highly expressed in all proliferative tissues, and its activity is key for the maintenance of genomic integrity (5). FEN1 has been identified as a cancer susceptibility gene, and mutations in it have been linked to a number of genetic diseases, such as EM map myotonic dystrophy, Huntington disease, several ataxias, fragile X syndrome, and cancer (6)(7)(8)(9)(10).…”