FEN1

Fig1. Structures of hFEN1 without DNA. (L David Finger, 2012)

What is FEN1 protein?

FEN1 (flap structure-specific endonuclease 1) gene is a protein coding gene which situated on the long arm of chromosome 11 at locus 11q12. FEN-1, also known as Flap structure-specific endonuclease 1, removes 5" overhanging flaps in DNA repair and processes the 5" ends of Okazaki fragments in lagging strand DNA synthesis. The protein is a member of the XPG/RAD2 endonuclease family and is one of ten proteins essential for cell-free DNA replication. The FEN1 protein is consisted of 380 amino acids and its molecular mass is approximately 42.6 kDa.

What is the function of FEN1 protein?

The FEN1 protein is a key DNA repair enzyme that plays an important role in cell division and DNA replication. The main functions of FEN1 include: excision of RNA primers, excision of single-stranded DNA ends, participation in long patch base excision repair, and maintenance of genome stability.

FEN1 Related Signaling Pathway

The signaling pathways involved in FEN1 protein mainly include DNA repair pathway and apoptosis pathway. On the one hand, it is involved in DNA repair pathways such as nucleotide excision repair (NER) and subcutaneous cleavage (SSB), helping to remove damaged bases or DNA forks on the DNA and restore the normal structure of the DNA. On the other hand, FEN1 is involved in the cleavage of nuclear DNA and the repair of DNA fragments during apoptosis.

FEN1 Related Diseases

The abnormal expression or mutation of FEN1 is associated with the occurrence and development of various malignant tumors such as breast cancer, liver cancer and colorectal cancer. It is also associated with neurodegenerative and immune diseases, liver disease, lung disease, and cardiovascular diseases, and FEN1 gene mutations are associated with the occurrence of some genetic diseases such as Xeroderma pigmentosum.

Fig2. FEN1 protein expression in pan-cancer tissues and paired nontumor samples. FEN1 protein was upregulated in tumor tissues. (Yingying Zhang, 2020)

Bioapplications of FEN1

FEN1 exhibits weak exonuclease activity in vitro, but is primarily dependent on its endonuclease activity for its function in the cell. This property can be exploited to develop highly sensitive bioassays for diagnosing diseases or monitoring specific DNA sequences in environmental samples. In addition, it plays an important role in gene editing, DNA repair mechanism research, DNA synthesis and modification.

Case study 1: Lu Xu, 2020

Flap endonuclease‑1 (FEN1), a structure‑specific nuclease participating in DNA replication and repair processes, has been confirmed to promote the proliferation and drug resistance of tumor cells. However, the biological functions of FEN1 in cancer cell migration and invasion have not been defined. In the present study, using online database analysis and immunohistochemistry of the specimens, it was found that FEN1 expression was associated with a highly invasive triple‑negative breast cancer (TNBC) subtype in both breast cancer samples from the Oncomine database and from patients recruited into the study. Furthermore, FEN1 was an important biomarker of lymph node metastasis and poor prognosis in patients with TNBC. FEN1 promoted migration of TNBC cell lines and FEN1 knockdown reduced the number of spontaneous lung metastasis in vivo. PLK4 was further identified as a critical target of FEN1 mediating TNBC cell migration, by regulating actin cytoskeleton rearrangement.

Fig1. The efficiency of FEN1 knockdown and overexpression was confirmed using western blot analysis

Fig2. Western blot analysis of MMP or endothelial‑mesenchymal transistion‑associated proteins in the MDA‑MB‑231 cell line transfected with the shFEN1 plasmid or FEN1 plasmid.

Case study 2: Yingying Zhang, 2020

Studies show that patients with hepatocellular carcinoma (HCC) have poor prognosis, particularly when patients are diagnosed at late stages of the disease development. The flap endonuclease 1 (FEN1) gene is overexpressed in multiple malignant tumors and may promote tumor aggressiveness. However, its expression profile and functional roles in HCC are still unclear.

The expression of FEN1 in HCC was evaluated using HCC mRNA expression data from TCGA and GEO databases. Kaplan-Meier analysis and univariate and multivariate Cox regression analyses were used to determine the correlation between FEN1 expression and survival rate of HCC patients. The molecular mechanism and biological functions of FEN1 in HCC were predicted using functional and pathway enrichment analysis in vitro experiments. The results showed that FEN1 was overexpressed in multiple HCC cohorts at both mRNA and protein levels. Furthermore, knocking down FEN1 resulted in suppressed cell proliferation and migration in vitro. This could have been due to regulation expressions of c-Myc, survivin, and cyclin D1 genes, indicating that FEN1 may function as an oncogene through its role in the cell cycle and DNA replication pathway.

Fig3. Knockdown of FEN1 in Hep-3b and Hep-G2 significantly decreased cell proliferation compared with si-NC cells, performed by the CCK-8 assay

Fig4. Protein levels of FEN1, c-Myc, survivin, and cyclin D1 after knockdown by si-FEN1. FEN1: flap endonuclease 1; HCC: hepatocellular carcinoma.

FEN1 has several biochemical functions, for example, 5-3 exonuclease activity,5-flap endonuclease activity,DNA binding. Some of the functions are cooperated with other proteins, some of the functions could acted by FEN1 itself. We selected most functions FEN1 had, and list some proteins which have the same functions with FEN1. You can find most of the proteins on our site.

FEN1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with FEN1 here. Most of them are supplied by our site. Hope this information will be useful for your research of FEN1.

WRN;PCNA;BLM;MUS81