7YV4

Crystal structure of human UCHL3 in complex with Farrerol

7YV4 の概要

• エントリーDOI: 10.2210/pdb7yv4/pdb
• 分子名称: Ubiquitin carboxyl-terminal hydrolase isozyme L3, (2~{S})-2-(4-hydroxyphenyl)-6,8-dimethyl-5,7-bis(oxidanyl)-2,3-dihydrochromen-4-one (3 entities in total)
• 機能のキーワード: activator, complex, ubiquitinase, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26513.88

構造登録者

Mao, Z.Y.,Xu, X.J.,Zhang, W.T. (登録日: 2022-08-18, 公開日: 2023-04-19, 最終更新日: 2023-11-29)

主引用文献

Zhang, W.,Wang, M.,Song, Z.,Fu, Q.,Chen, J.,Zhang, W.,Gao, S.,Sun, X.,Yang, G.,Zhang, Q.,Yang, J.,Tang, H.,Wang, H.,Kou, X.,Wang, H.,Mao, Z.,Xu, X.,Gao, S.,Jiang, Y.
Farrerol directly activates the deubiqutinase UCHL3 to promote DNA repair and reprogramming when mediated by somatic cell nuclear transfer.
Nat Commun, 14:1838-1838, 2023

PubMed Abstract: Farrerol, a natural flavanone, promotes homologous recombination (HR) repair to improve genome-editing efficiency, but the specific protein that farrerol directly targets to regulate HR repair and the underlying molecular mechanisms have not been determined. Here, we find that the deubiquitinase UCHL3 is the direct target of farrerol. Mechanistically, farrerol enhanced the deubiquitinase activity of UCHL3 to promote RAD51 deubiquitination, thereby improving HR repair. Importantly, we find that embryos of somatic cell nuclear transfer (SCNT) exhibited defective HR repair, increased genomic instability and aneuploidy, and that the farrerol treatment post nuclear transfer enhances HR repair, restores transcriptional and epigenetic network, and promotes SCNT embryo development. Ablating UCHL3 significantly attenuates farrerol-mediated stimulation in HR and SCNT embryo development. In summary, we identify farrerol as an activator of the deubiquitinase UCHL3, highlighted the importance of HR and epigenetic changes in SCNT reprogramming and provide a feasible method to promote SCNT efficiency.

PubMed: 37012254
DOI: 10.1038/s41467-023-37576-9

実験手法

X-RAY DIFFRACTION (1.58 Å)