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Mismatch repair proteins play a role in ATR activation upon temozolomide treatment in MGMT-methylated glioblastoma

The methylation status of the O(6)-methylguanine methyltransferase (MGMT) gene promoter has been widely accepted as a prognostic biomarker for treatment with the alkylator, temozolomide (TMZ). In the absence of promoter methylation, the MGMT enzyme removes O(6)-methylguanine (O(6)-meG) lesions. In t...

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Autores principales: Ganesa, Sachita, Sule, Amrita, Sundaram, Ranjini K., Bindra, Ranjit S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987098/
https://www.ncbi.nlm.nih.gov/pubmed/35388070
http://dx.doi.org/10.1038/s41598-022-09614-x
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author Ganesa, Sachita
Sule, Amrita
Sundaram, Ranjini K.
Bindra, Ranjit S.
author_facet Ganesa, Sachita
Sule, Amrita
Sundaram, Ranjini K.
Bindra, Ranjit S.
author_sort Ganesa, Sachita
collection PubMed
description The methylation status of the O(6)-methylguanine methyltransferase (MGMT) gene promoter has been widely accepted as a prognostic biomarker for treatment with the alkylator, temozolomide (TMZ). In the absence of promoter methylation, the MGMT enzyme removes O(6)-methylguanine (O(6)-meG) lesions. In the setting of MGMT-promoter methylation (MGMT-), the O(6)-meG lesion activates the mismatch repair (MMR) pathway which functions to remove the damage. Our group reported that loss of MGMT expression via MGMT promoter silencing modulates activation of ataxia telangiectasia and RAD3 related protein (ATR) in response to TMZ treatment, which is associated with synergistic tumor-cell killing. Whether or not MMR proteins are involved in ATR activation in MGMT-cells upon alkylation damage remains poorly understood. To investigate the function of MMR in ATR activation, we created isogenic cell lines with knockdowns of the individual human MMR proteins MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), MutS homolog 3 (MSH3), MutL homolog 1 (MLH1), and PMS1 homolog 2 (PMS2). Here, we demonstrate that MSH2, MSH6, MLH1 and PMS2, specifically, are involved in the activation of the ATR axis after TMZ exposure, whereas MSH3 is likely not. This study elucidates a potential mechanistic understanding of how the MMR system is involved in ATR activation by TMZ in glioblastoma cells, which is important for targeting MMR-mutated cancers.
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spelling pubmed-89870982022-04-08 Mismatch repair proteins play a role in ATR activation upon temozolomide treatment in MGMT-methylated glioblastoma Ganesa, Sachita Sule, Amrita Sundaram, Ranjini K. Bindra, Ranjit S. Sci Rep Article The methylation status of the O(6)-methylguanine methyltransferase (MGMT) gene promoter has been widely accepted as a prognostic biomarker for treatment with the alkylator, temozolomide (TMZ). In the absence of promoter methylation, the MGMT enzyme removes O(6)-methylguanine (O(6)-meG) lesions. In the setting of MGMT-promoter methylation (MGMT-), the O(6)-meG lesion activates the mismatch repair (MMR) pathway which functions to remove the damage. Our group reported that loss of MGMT expression via MGMT promoter silencing modulates activation of ataxia telangiectasia and RAD3 related protein (ATR) in response to TMZ treatment, which is associated with synergistic tumor-cell killing. Whether or not MMR proteins are involved in ATR activation in MGMT-cells upon alkylation damage remains poorly understood. To investigate the function of MMR in ATR activation, we created isogenic cell lines with knockdowns of the individual human MMR proteins MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), MutS homolog 3 (MSH3), MutL homolog 1 (MLH1), and PMS1 homolog 2 (PMS2). Here, we demonstrate that MSH2, MSH6, MLH1 and PMS2, specifically, are involved in the activation of the ATR axis after TMZ exposure, whereas MSH3 is likely not. This study elucidates a potential mechanistic understanding of how the MMR system is involved in ATR activation by TMZ in glioblastoma cells, which is important for targeting MMR-mutated cancers. Nature Publishing Group UK 2022-04-06 /pmc/articles/PMC8987098/ /pubmed/35388070 http://dx.doi.org/10.1038/s41598-022-09614-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ganesa, Sachita
Sule, Amrita
Sundaram, Ranjini K.
Bindra, Ranjit S.
Mismatch repair proteins play a role in ATR activation upon temozolomide treatment in MGMT-methylated glioblastoma
title Mismatch repair proteins play a role in ATR activation upon temozolomide treatment in MGMT-methylated glioblastoma
title_full Mismatch repair proteins play a role in ATR activation upon temozolomide treatment in MGMT-methylated glioblastoma
title_fullStr Mismatch repair proteins play a role in ATR activation upon temozolomide treatment in MGMT-methylated glioblastoma
title_full_unstemmed Mismatch repair proteins play a role in ATR activation upon temozolomide treatment in MGMT-methylated glioblastoma
title_short Mismatch repair proteins play a role in ATR activation upon temozolomide treatment in MGMT-methylated glioblastoma
title_sort mismatch repair proteins play a role in atr activation upon temozolomide treatment in mgmt-methylated glioblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987098/
https://www.ncbi.nlm.nih.gov/pubmed/35388070
http://dx.doi.org/10.1038/s41598-022-09614-x
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