Fbh1-KO Mouse

Fbh1, or F-box DNA helicase 1, is a member of the UvrD family of DNA helicases. It plays crucial roles in the DNA damage response, especially in the regulation of cell responses to replicative stress [2,4,6]. FBH1 is involved in pathways related to DNA replication fork processing, homologous recombination, and cell cycle checkpoint control, which are essential for maintaining genome integrity [2,3,4,7].

FBH1-deficient cells show a reduction in ssDNA and double-strand break signaling when treated with WEE1 inhibitors, indicating its requirement for the induction of replication stress response [1,5]. However, FBH1-deficiency sensitizes cells to WEE1 inhibition by increasing mitotic catastrophe, suggesting that loss of FBH1 leads to replication-associated damage that needs the WEE1-dependent G2 checkpoint for repair [1,5]. Also, FBH1 depletion promotes UV-mediated transformation of human melanocytes, and its inactivation may contribute to oncogenic transformation [6].

In conclusion, FBH1 is essential for regulating the cell's response to replication stress, maintaining genome integrity, and preventing oncogenic transformation. Studies on FBH1-deficient cells have revealed its role in replication-associated damage repair and cell cycle checkpoint control, which are relevant to cancer therapy, especially in the context of WEE1 inhibition [1,5,6].

References:

1. Jennings, Lucy, Walters, Heather Andrews, Mason, Jennifer M. 2023. FBH1 deficiency sensitizes cells to WEE1 inhibition by promoting mitotic catastrophe. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.05.15.540841. https://pubmed.ncbi.nlm.nih.gov/37292855/

2. Liu, Jiuyang, Chaves-Arquero, Belén, Wei, Pengcheng, Blanco, Francisco J, Kutateladze, Tatiana G. 2023. Molecular insight into the PCNA-binding mode of FBH1. In Structure (London, England : 1993), 31, 511-517.e3. doi:10.1016/j.str.2023.03.004. https://pubmed.ncbi.nlm.nih.gov/36990095/

3. Liu, Guangxue, Li, Jimin, He, Boxue, Zhang, Xinghua, Chen, Xuefeng. 2023. Bre1/RNF20 promotes Rad51-mediated strand exchange and antagonizes the Srs2/FBH1 helicases. In Nature communications, 14, 3024. doi:10.1038/s41467-023-38617-z. https://pubmed.ncbi.nlm.nih.gov/37230987/

4. Hawks, Alexandra L, Bergmann, Amy, McCraw, Tyler J, Mason, Jennifer M. 2023. UBC13-mediated template switching promotes replication stress resistance in FBH1-deficient cells. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.09.04.556280. https://pubmed.ncbi.nlm.nih.gov/37732269/

5. Jennings, Lucy, Walters, Heather Andrews, McCraw, Tyler J, Turner, Joshua L, Mason, Jennifer M. 2023. FBH1 deficiency sensitizes cells to WEE1 inhibition by promoting mitotic catastrophe. In DNA repair, 133, 103611. doi:10.1016/j.dnarep.2023.103611. https://pubmed.ncbi.nlm.nih.gov/38103522/

6. Jeong, Yeon-Tae, Cermak, Lukas, Guijarro, Maria V, Hernando, Eva, Pagano, Michele. 2013. FBH1 protects melanocytes from transformation and is deregulated in melanomas. In Cell cycle (Georgetown, Tex.), 12, 1128-32. doi:10.4161/cc.24165. https://pubmed.ncbi.nlm.nih.gov/23466708/

7. Fugger, Kasper, Mistrik, Martin, Neelsen, Kai J, Hickson, Ian D, Sørensen, Claus Storgaard. 2015. FBH1 Catalyzes Regression of Stalled Replication Forks. In Cell reports, 10, 1749-1757. doi:10.1016/j.celrep.2015.02.028. https://pubmed.ncbi.nlm.nih.gov/25772361/