CAMK2D serves as a molecular scaffold for RNF8-MAD2 complex to induce mitotic checkpoint in glioma

CAMK2D serves as a molecular scaffold for RNF8-MAD2 complex to induce mitotic checkpoint in glioma

MAD2 is a spindle assembly checkpoint protein that participates in the formation of mitotic checkpoint complex, which blocks mitotic progression. RNF8, an established DNA damage response protein, has been implicated in mitotic checkpoint regulation but its exact role remains poorly understood. Here,...

Full description

Saved in:
Bibliographic Details
Main Authors: Chuah, You Heng, Tay, Emmy Xue Yun, Grinchuk, Oleg V., Yoon, Jeehyun, Feng, Jia, Kannan, Srinivasaraghavan, Robert, Matius, Jakhar, Rekha, Liang, Yajing, Lee, Bernice Woon Li, Wang, Loo Chien, Lim, Yan Ting, Zhao, Tianyun, Sobota, Radoslaw M., Lu, Guang, Low, Boon Chuan, Crasta, Karen Carmelina, Verma, Chandra Shekhar, Lin, Zhewang, Ong, Derrick Sek Tong
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2024
Subjects:
Medicine, Health and Life Sciences
CAMK2D protein
Glioma
Online Access:https://hdl.handle.net/10356/174262
Tags: Add Tag
No Tags, Be the first to tag this record!
Institution: Nanyang Technological University
Language: English
Description
Summary:MAD2 is a spindle assembly checkpoint protein that participates in the formation of mitotic checkpoint complex, which blocks mitotic progression. RNF8, an established DNA damage response protein, has been implicated in mitotic checkpoint regulation but its exact role remains poorly understood. Here, RNF8 proximity proteomics uncovered a role of RNF8-MAD2 in generating the mitotic checkpoint signal. Specifically, RNF8 competes with a small pool of p31comet for binding to the closed conformer of MAD2 via its RING domain, while CAMK2D serves as a molecular scaffold to concentrate the RNF8-MAD2 complex via transient/weak interactions between its p-Thr287 and RNF8's FHA domain. Accordingly, RNF8 overexpression impairs glioma stem cell (GSC) mitotic progression in a FHA- and RING-dependent manner. Importantly, low RNF8 expression correlates with inferior glioma outcome and RNF8 overexpression impedes GSC tumorigenicity. Last, we identify PLK1 inhibitor that mimics RNF8 overexpression using a chemical biology approach, and demonstrate a PLK1/HSP90 inhibitor combination that synergistically reduces GSC proliferation and stemness. Thus, our study has unveiled a previously unrecognized CAMK2D-RNF8-MAD2 complex in regulating mitotic checkpoint with relevance to gliomas, which is therapeutically targetable.

Similar Items