7KLZ

Structure of SPOP MATH domain in complex with a Geminin peptide

7KLZ の概要

• エントリーDOI: 10.2210/pdb7klz/pdb
• 分子名称: Speckle-type POZ protein, Geminin peptide, PHOSPHATE ION (3 entities in total)
• 機能のキーワード: spop, geminin, math domain, e3 ubiquitin ligase, dna damage response, dna replication, protein binding
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 35960.98

構造登録者

Cui, G.,Botuyan, M.V.,Mer, G. (登録日: 2020-11-01, 公開日: 2021-08-18, 最終更新日: 2024-10-23)

主引用文献

Ma, J.,Shi, Q.,Cui, G.,Sheng, H.,Botuyan, M.V.,Zhou, Y.,Yan, Y.,He, Y.,Wang, L.,Wang, Y.,Mer, G.,Ye, D.,Wang, C.,Huang, H.
SPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition.
Nat Commun, 12:5779-5779, 2021

PubMed Abstract: Geminin and its binding partner Cdt1 are essential for the regulation of DNA replication. Here we show that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP binds Geminin at endogenous level and regulates DNA replication. SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. This poly-ubiquitination of Geminin prevents DNA replication over-firing by indirectly blocking the association of Cdt1 with the MCM protein complex, an interaction required for DNA unwinding and replication. SPOP is frequently mutated in certain human cancer types and implicated in tumorigenesis. We show that cancer-associated SPOP mutations impair Geminin K27-linked poly-ubiquitination and induce replication origin over-firing and re-replication. The replication stress caused by SPOP mutations triggers replication catastrophe and cell death upon ATR inhibition. Our results reveal a tumor suppressor role of SPOP in preventing DNA replication over-firing and genome instability and suggest that SPOP-mutated tumors may be susceptible to ATR inhibitor therapy.

PubMed: 34599168
DOI: 10.1038/s41467-021-26049-6

実験手法

X-RAY DIFFRACTION (3.4 Å)