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PARP1-MGMT complex underpins pathway crosstalk in O(6)-methylguanine repair

DNA lesions induced by alkylating agents are repaired by two canonical mechanisms, base excision repair dependent on poly(ADP) ribose polymerase 1 (PARP1) and the other mediated by O(6)-methylguanine (O(6)meG)-DNA methyltransferase (MGMT) in a single-step catalysis of alkyl-group removal. O(6)meG is...

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Autores principales: Cropper, Jodie D., Alimbetov, Dauren S., Brown, Kevin T. G., Likhotvorik, Rostislav I., Robles, Andrew J., Guerra, James T., He, Boxue, Chen, Yidong, Kwon, Youngho, Kurmasheva, Raushan T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9563463/
https://www.ncbi.nlm.nih.gov/pubmed/36242092
http://dx.doi.org/10.1186/s13045-022-01367-4
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author Cropper, Jodie D.
Alimbetov, Dauren S.
Brown, Kevin T. G.
Likhotvorik, Rostislav I.
Robles, Andrew J.
Guerra, James T.
He, Boxue
Chen, Yidong
Kwon, Youngho
Kurmasheva, Raushan T.
author_facet Cropper, Jodie D.
Alimbetov, Dauren S.
Brown, Kevin T. G.
Likhotvorik, Rostislav I.
Robles, Andrew J.
Guerra, James T.
He, Boxue
Chen, Yidong
Kwon, Youngho
Kurmasheva, Raushan T.
author_sort Cropper, Jodie D.
collection PubMed
description DNA lesions induced by alkylating agents are repaired by two canonical mechanisms, base excision repair dependent on poly(ADP) ribose polymerase 1 (PARP1) and the other mediated by O(6)-methylguanine (O(6)meG)-DNA methyltransferase (MGMT) in a single-step catalysis of alkyl-group removal. O(6)meG is the most cytotoxic and mutagenic lesion among the methyl adducts induced by alkylating agents. Although it can accomplish the dealkylation reaction all by itself as a single protein without associating with other repair proteins, evidence is accumulating that MGMT can form complexes with repair proteins and is highly regulated by a variety of post-translational modifications, such as phosphorylation, ubiquitination, and others. Here, we show that PARP1 and MGMT proteins interact directly in a non-catalytic manner, that MGMT is subject to PARylation by PARP1 after DNA damage, and that the O(6)meG repair is enhanced upon MGMT PARylation. We provide the first evidence for the direct DNA-independent PARP1-MGMT interaction. Further, PARP1 and MGMT proteins also interact via PARylation of MGMT leading to formation of a novel DNA damage inducible PARP1-MGMT protein complex. This catalytic interaction activates O(6)meG repair underpinning the functional crosstalk between base excision and MGMT-mediated DNA repair mechanisms. Furthermore, clinically relevant ‘chronic’ temozolomide exposure induced PARylation of MGMT and increased binding of PARP1 and MGMT to chromatin in cells. Thus, we provide the first mechanistic description of physical interaction between PARP1 and MGMT and their functional cooperation through PARylation for activation of O(6)meG repair. Hence, the PARP1-MGMT protein complex could be targeted for the development of advanced and more effective cancer therapeutics, particularly for cancers sensitive to PARP1 and MGMT inhibition. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-022-01367-4.
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spelling pubmed-95634632022-10-15 PARP1-MGMT complex underpins pathway crosstalk in O(6)-methylguanine repair Cropper, Jodie D. Alimbetov, Dauren S. Brown, Kevin T. G. Likhotvorik, Rostislav I. Robles, Andrew J. Guerra, James T. He, Boxue Chen, Yidong Kwon, Youngho Kurmasheva, Raushan T. J Hematol Oncol Correspondence DNA lesions induced by alkylating agents are repaired by two canonical mechanisms, base excision repair dependent on poly(ADP) ribose polymerase 1 (PARP1) and the other mediated by O(6)-methylguanine (O(6)meG)-DNA methyltransferase (MGMT) in a single-step catalysis of alkyl-group removal. O(6)meG is the most cytotoxic and mutagenic lesion among the methyl adducts induced by alkylating agents. Although it can accomplish the dealkylation reaction all by itself as a single protein without associating with other repair proteins, evidence is accumulating that MGMT can form complexes with repair proteins and is highly regulated by a variety of post-translational modifications, such as phosphorylation, ubiquitination, and others. Here, we show that PARP1 and MGMT proteins interact directly in a non-catalytic manner, that MGMT is subject to PARylation by PARP1 after DNA damage, and that the O(6)meG repair is enhanced upon MGMT PARylation. We provide the first evidence for the direct DNA-independent PARP1-MGMT interaction. Further, PARP1 and MGMT proteins also interact via PARylation of MGMT leading to formation of a novel DNA damage inducible PARP1-MGMT protein complex. This catalytic interaction activates O(6)meG repair underpinning the functional crosstalk between base excision and MGMT-mediated DNA repair mechanisms. Furthermore, clinically relevant ‘chronic’ temozolomide exposure induced PARylation of MGMT and increased binding of PARP1 and MGMT to chromatin in cells. Thus, we provide the first mechanistic description of physical interaction between PARP1 and MGMT and their functional cooperation through PARylation for activation of O(6)meG repair. Hence, the PARP1-MGMT protein complex could be targeted for the development of advanced and more effective cancer therapeutics, particularly for cancers sensitive to PARP1 and MGMT inhibition. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-022-01367-4. BioMed Central 2022-10-14 /pmc/articles/PMC9563463/ /pubmed/36242092 http://dx.doi.org/10.1186/s13045-022-01367-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Correspondence
Cropper, Jodie D.
Alimbetov, Dauren S.
Brown, Kevin T. G.
Likhotvorik, Rostislav I.
Robles, Andrew J.
Guerra, James T.
He, Boxue
Chen, Yidong
Kwon, Youngho
Kurmasheva, Raushan T.
PARP1-MGMT complex underpins pathway crosstalk in O(6)-methylguanine repair
title PARP1-MGMT complex underpins pathway crosstalk in O(6)-methylguanine repair
title_full PARP1-MGMT complex underpins pathway crosstalk in O(6)-methylguanine repair
title_fullStr PARP1-MGMT complex underpins pathway crosstalk in O(6)-methylguanine repair
title_full_unstemmed PARP1-MGMT complex underpins pathway crosstalk in O(6)-methylguanine repair
title_short PARP1-MGMT complex underpins pathway crosstalk in O(6)-methylguanine repair
title_sort parp1-mgmt complex underpins pathway crosstalk in o(6)-methylguanine repair
topic Correspondence
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9563463/
https://www.ncbi.nlm.nih.gov/pubmed/36242092
http://dx.doi.org/10.1186/s13045-022-01367-4
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