Figure - PMC

Skip to main content

An official website of the United States government

Here's how you know

Here's how you know

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

View full-text article in PMC

. 2022 Apr 6;12:5827. doi: 10.1038/s41598-022-09614-x

Search in PMC
Search in PubMed
View in NLM Catalog
Add to search

© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

PMC Copyright notice

MMR is likely implicated in the entire ATR/CHK1 signaling axis. Synergy assays were performed between TMZ and AZD7762 in the newly created MMR-deficient LN229 isogenic cell lines in triplicate plates before being analyzed by Combenefit. Cells were treated for 6 days with the combination of inhibitors. (A) MGMT- cells that are MMR-proficient and (B) shMSH3 MGMT- cells exhibit some synergy upon treatment with TMZ and AZD7762. (C) shMSH2, (D) shMSH6, (E) shMLH1, and (F) shPMS2 MGMT- cells do not display synergy for the combination of TMZ and AZD7762. This indicates that the knockdown of MSH2, MSH6, MLH1, and PMS2 adversely affects synergy between TMZ and AZD7762, suggesting a role for these proteins in ATR-CHK1 signaling. (G) Western blot of MGMT- and shMSH2 MGMT- cells showing the kinetics of ATR activation through pCHK1 levels after 12.5 µM of TMZ treatment for the time course indicated. From the densitometry analysis of this blot, there is a robust increase in pCHK1 levels over time in the MGMT- MMR-proficient cells, but not in the shMSH2 cells, suggesting that MSH2 is required for ATR activation and signaling to CHK1. The densitometry analysis is based upon the pCHK1 levels from this representative western blot. Full length blots are shown in the supplemental.