Fen1, also known as Flap endonuclease 1, is a core protein in the base excision repair (BER) pathway and is involved in Okazaki fragment maturation during DNA replication [2]. It belongs to the Rad2 structure-specific nuclease family and has 5' flap endonuclease, 5'-3' exonuclease and gap-endonuclease activities, allowing it to participate in multiple DNA metabolic pathways such as stalled replication fork rescue, telomere maintenance, and apoptotic DNA fragmentation [5]. It is crucial for maintaining genomic stability and integrity [3].

Genetic screens have identified FEN1 as a synthetic lethal gene with both BRCA1 and BRCA2 loss of function. BRCA2-deficient cells require the 5' flap endonuclease but not the 5'-3' exonuclease activity of Fen1, and chemically inhibiting Fen1 selectively targets BRCA-deficient cells. Also, Fen1 participates in microhomology-mediated end-joining (MMEJ), highlighting MMEJ as a collateral repair pathway in homologous recombination (HR) deficiency [1]. Abnormal expression or mutation of FEN1 in cells can cause a series of pathological responses, leading to various diseases, especially cancers. For example, in hepatocellular carcinoma, FEN1 upregulation mediated by SUMO2 promotes cancer stemness by antagonizing proteasomal degradation [3]. In cholangiocarcinoma, FEN1 promotes cancer progression by regulating the Wnt/β-catenin signaling pathway [4].

In conclusion, Fen1 is essential for DNA repair and replication-related processes. Model-based research, especially in the context of BRCA-deficient backgrounds and various cancer models, has revealed its role in DNA repair pathways and cancer development. Understanding Fen1's functions provides potential therapeutic targets for treating cancers, especially those related to BRCA-deficiency.

References:

1. Mengwasser, Kristen E, Adeyemi, Richard O, Leng, Yumei, D'Andrea, Alan D, Elledge, Stephen J. 2019. Genetic Screens Reveal FEN1 and APEX2 as BRCA2 Synthetic Lethal Targets. In Molecular cell, 73, 885-899.e6. doi:10.1016/j.molcel.2018.12.008. https://pubmed.ncbi.nlm.nih.gov/30686591/

2. Yang, Fan, Hu, Zhigang, Guo, Zhigang. 2022. Small-Molecule Inhibitors Targeting FEN1 for Cancer Therapy. In Biomolecules, 12, . doi:10.3390/biom12071007. https://pubmed.ncbi.nlm.nih.gov/35883563/

3. Peng, Zhenxiang, Wang, Shuling, Wen, Diguang, Lv, Lin, Li, Chuanfei. 2024. FEN1 upregulation mediated by SUMO2 via antagonizing proteasomal degradation promotes hepatocellular carcinoma stemness. In Translational oncology, 44, 101916. doi:10.1016/j.tranon.2024.101916. https://pubmed.ncbi.nlm.nih.gov/38513457/

4. Yuwei, Xie, Bingzi, Dong, Zhaowei, Sun, Jingyu, Cao, Chengzhan, Zhu. 2023. FEN1 promotes cancer progression of cholangiocarcinoma by regulating the Wnt/β-catenin signaling pathway. In Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 56, 695-704. doi:10.1016/j.dld.2023.08.050. https://pubmed.ncbi.nlm.nih.gov/37648642/

5. Zheng, Li, Jia, Jia, Finger, L David, Zer, Cindy, Shen, Binghui. 2010. Functional regulation of FEN1 nuclease and its link to cancer. In Nucleic acids research, 39, 781-94. doi:10.1093/nar/gkq884. https://pubmed.ncbi.nlm.nih.gov/20929870/