Flap structure-specific endonuclease 1

Flap structure-specific endonuclease 1 (FEN1) is a protein that in humans is encoded by the FEN1 gene. FEN1 plays a critical role in DNA replication and repair, and it is essential for cell viability and genome stability. This enzyme belongs to the flap endonuclease-1 family and is involved in the processing of DNA flaps during replication and repair, ensuring the accuracy of DNA duplication and the maintenance of genomic integrity.

Function

FEN1 is a structure-specific nuclease that cleaves flap structures that arise during various DNA metabolism processes such as replication, repair, and recombination. It is particularly important for the removal of 5' overhangs in Okazaki fragments during lagging-strand DNA synthesis, thus facilitating the joining of Okazaki fragments. FEN1's activity is crucial for the base excision repair (BER) pathway, where it removes flap structures formed during the repair of damaged or erroneous DNA bases. Additionally, FEN1 participates in the resolution of stalled replication forks and the maintenance of telomeres, contributing to overall genomic stability.

Structure

The structure of FEN1 reveals a highly conserved nuclease domain that recognizes and binds to the flap structure of DNA. This domain allows FEN1 to cleave the flap structure accurately, ensuring efficient and precise processing of DNA intermediates. The enzyme's structure is adapted to interact specifically with single-stranded/double-stranded DNA junctions, highlighting its role in recognizing and resolving specific DNA structures that arise during replication and repair processes.

Clinical Significance

Mutations in the FEN1 gene have been associated with various cancers, underscoring the enzyme's role in maintaining genomic stability. Deficiencies in FEN1 function can lead to an accumulation of DNA replication errors and increased susceptibility to genomic instability, contributing to tumorigenesis. Furthermore, FEN1 has been studied as a potential target for cancer therapy, with inhibitors being explored to enhance the efficacy of chemotherapy by exploiting the dependency of cancer cells on FEN1 for survival and proliferation.

Interactions

FEN1 interacts with several proteins involved in DNA replication and repair, including Proliferating Cell Nuclear Antigen (PCNA), which is essential for its function in Okazaki fragment processing. The interaction with PCNA not only stimulates FEN1's nuclease activity but also targets it to replication forks and repair sites. Other notable interactions include those with BRCA1, WRN, and DNA ligase I, highlighting the enzyme's integration into the complex network of DNA metabolism.

See Also

• DNA replication
• DNA repair
• Okazaki fragments
• Base excision repair
• Proliferating Cell Nuclear Antigen