Flap Endonuclease 1 (FEN1) is a protein found in the cells of various organisms, including humans. It functions as a specialized enzyme, maintaining the integrity of our genetic material. It acts as a molecular “clean-up” crew, ensuring DNA remains accurate and free from errors. Understanding FEN1’s activities provides insight into how cells safeguard their genetic blueprint.
FEN1’s Essential Role in DNA Processes
FEN1 performs enzymatic actions central to DNA metabolism. During DNA replication, FEN1 is particularly active on the lagging strand. Here, DNA is synthesized in short segments called Okazaki fragments. FEN1 removes the RNA primers that initiate these fragments, along with any displaced single-stranded DNA “flaps,” preparing the DNA for seamless joining by other enzymes. It achieves this by binding to the flap’s base and threading the 5′ end through its active site for cleavage.
Beyond replication, FEN1 is involved in several DNA repair pathways. In long-patch base excision repair (BER), FEN1 removes damaged or incorrect bases that have been excised, leaving a gap that needs to be filled. FEN1 also helps resolve stalled replication forks that can arise from DNA damage, such as those caused by UV irradiation. Its ability to cleave specific DNA structures, including 5′ overhanging flaps, makes it versatile in these repair processes.
How FEN1 Maintains Genomic Stability
FEN1’s actions are directly linked to maintaining genomic stability, which is the integrity and accuracy of a cell’s genetic information. By efficiently processing DNA during replication and repair, FEN1 prevents the accumulation of errors that could lead to mutations or chromosomal rearrangements. For example, FEN1 helps prevent sequence duplications and expansions of repetitive DNA sequences, which can destabilize the genome. It also contributes to maintaining the length of telomeres, the protective caps at the ends of chromosomes. The absence or malfunction of FEN1 can lead to increased sensitivity to DNA-damaging agents, highlighting its protective role.
FEN1’s Link to Health and Disease
Dysfunction of FEN1 has implications for human health, particularly its connection to diseases characterized by genomic instability. Errors in FEN1 function can lead to an accumulation of mutations that contribute to the development and progression of various cancers. Overexpression of FEN1 has been observed in the majority of breast, prostate, stomach, and lung cancers, as well as neuroblastomas and pancreatic cancers.
FEN1 is also involved in an inaccurate DNA repair pathway called microhomology-mediated end joining (MMEJ), which can introduce small deletions and is thus mutagenic. In certain cancers, such as those with defects in homologous recombination repair (e.g., BRCA1 or BRCA2 mutations), inhibiting FEN1 can lead to synthetic lethality, meaning the combined deficiencies are fatal to the cancer cells. Beyond cancer, FEN1 is implicated in certain neurodegenerative diseases, where its activity can influence the instability of trinucleotide repeat sequences. Research continues to explore FEN1 as a potential therapeutic target or biomarker for disease diagnosis and treatment.