Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription

Chromosomal instability is a key feature in cancer progression. Recently we have reported that BRCA1 regulates the transcription of several genes in prostate cancer, including ATM (ataxia telangiectasia mutated). Although it is well accepted that ATM is a pivotal mediator in genotoxic stress, it is...

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Autores principales:	Moiola, Cristian Pablo, De Luca, Paola, Vázquez, Elba Susana, De Siervi, Adriana
Publicado:	2012
Materias:	ATM BRCA1 DNA damage Prostate cancer Transcription 2 morpholino 6 (1 thianthrenyl) 4 pyranone ATM protein BRCA1 associated ring domain protein 1 C terminal interacting protein doxorubicin etoposide histone H2AX methotrexate mitoxantrone protein transcription factor E2F1 unclassified drug article binding site cancer cell culture chromatin controlled study genetic transcription human human cell male positive feedback priority journal promoter region prostate cancer protein binding protein expression protein phosphorylation protein secretion transcription regulation Antibiotics, Antineoplastic BRCA1 Protein Carrier Proteins Cell Cycle Proteins Cell Line, Tumor DNA Damage DNA Repair DNA-Binding Proteins Doxorubicin E2F1 Transcription Factor Humans Morpholines Nuclear Proteins Promoter Regions, Genetic Protein Binding Protein Structure, Tertiary Protein-Serine-Threonine Kinases Pyrones Transcription, Genetic Tumor Suppressor Proteins Ataxia telangiectasia
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_10158987_v30_n3_p596_Moiola http://hdl.handle.net/20.500.12110/paper_10158987_v30_n3_p596_Moiola
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paper:paper_10158987_v30_n3_p596_Moiola
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spelling	paper:paper_10158987_v30_n3_p596_Moiola2023-06-08T15:59:47Z Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription Moiola, Cristian Pablo De Luca, Paola Vázquez, Elba Susana De Siervi, Adriana ATM BRCA1 DNA damage Prostate cancer Transcription 2 morpholino 6 (1 thianthrenyl) 4 pyranone ATM protein BRCA1 associated ring domain protein 1 C terminal interacting protein doxorubicin etoposide histone H2AX methotrexate mitoxantrone protein transcription factor E2F1 unclassified drug article binding site cancer cell culture chromatin controlled study DNA damage genetic transcription human human cell male positive feedback priority journal promoter region prostate cancer protein binding protein expression protein phosphorylation protein secretion transcription regulation Antibiotics, Antineoplastic BRCA1 Protein Carrier Proteins Cell Cycle Proteins Cell Line, Tumor DNA Damage DNA Repair DNA-Binding Proteins Doxorubicin E2F1 Transcription Factor Humans Morpholines Nuclear Proteins Promoter Regions, Genetic Protein Binding Protein Structure, Tertiary Protein-Serine-Threonine Kinases Pyrones Transcription, Genetic Tumor Suppressor Proteins Ataxia telangiectasia Chromosomal instability is a key feature in cancer progression. Recently we have reported that BRCA1 regulates the transcription of several genes in prostate cancer, including ATM (ataxia telangiectasia mutated). Although it is well accepted that ATM is a pivotal mediator in genotoxic stress, it is unknown whether ATM transcription is regulated during the molecular response to DNA damage. Here we investigate ATM transcription regulation in human prostate tumor PC3 cell line. We have found that doxorubicin and mitoxantrone repress ATM transcription in PC3 cells but etoposide and methotrexate do not affect ATM expression. We have demonstrated that BRCA1 binds to ATM promoter and after doxorubicin exposure, it is released. BRCA1 overexpression increases ATM transcription and this enhancement is abolished by BRCA1 depletion. Moreover, BRCA1-BRCT domain loss impairs the ability of BRCA1 to regulate ATM promoter activity, strongly suggesting that BRCT domain is essential for ATM regulation by BRCA1. BRCA1-overexpressing PC3 cells exposed to KU55933 ATM kinase inhibitor showed significant decreased ATM promoter activity compared to untreated cells, suggesting that ATM transcriptional regulation by BRCA1 is partially mediated by the ATM kinase activity. In addition, we have demonstrated E2F1 binding to ATM promoter before and after doxorubicin exposure. E2F1 overexpression diminishes ATM transcription after doxorubicin exposure which is impaired by E2F1 dominant negative mutants. Finally, the co-regulator of transcription CtIP increases ATM transcription. CtIP increases ATM transcription. Altogether, BRCA1/E2F1/CtIP binding to ATM promoter activates ATM transcription. Doxorubicin exposure releases BRCA1 and CtIP from ATM promoter still keeping E2F1 recruited and, in turn, represses ATM expression. Copyright © 2012 S. Karger AG, Basel. Fil:Moiola, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:De Luca, P. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Vazquez, E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:De Siervi, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2012 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_10158987_v30_n3_p596_Moiola http://hdl.handle.net/20.500.12110/paper_10158987_v30_n3_p596_Moiola
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	ATM BRCA1 DNA damage Prostate cancer Transcription 2 morpholino 6 (1 thianthrenyl) 4 pyranone ATM protein BRCA1 associated ring domain protein 1 C terminal interacting protein doxorubicin etoposide histone H2AX methotrexate mitoxantrone protein transcription factor E2F1 unclassified drug article binding site cancer cell culture chromatin controlled study DNA damage genetic transcription human human cell male positive feedback priority journal promoter region prostate cancer protein binding protein expression protein phosphorylation protein secretion transcription regulation Antibiotics, Antineoplastic BRCA1 Protein Carrier Proteins Cell Cycle Proteins Cell Line, Tumor DNA Damage DNA Repair DNA-Binding Proteins Doxorubicin E2F1 Transcription Factor Humans Morpholines Nuclear Proteins Promoter Regions, Genetic Protein Binding Protein Structure, Tertiary Protein-Serine-Threonine Kinases Pyrones Transcription, Genetic Tumor Suppressor Proteins Ataxia telangiectasia
spellingShingle	ATM BRCA1 DNA damage Prostate cancer Transcription 2 morpholino 6 (1 thianthrenyl) 4 pyranone ATM protein BRCA1 associated ring domain protein 1 C terminal interacting protein doxorubicin etoposide histone H2AX methotrexate mitoxantrone protein transcription factor E2F1 unclassified drug article binding site cancer cell culture chromatin controlled study DNA damage genetic transcription human human cell male positive feedback priority journal promoter region prostate cancer protein binding protein expression protein phosphorylation protein secretion transcription regulation Antibiotics, Antineoplastic BRCA1 Protein Carrier Proteins Cell Cycle Proteins Cell Line, Tumor DNA Damage DNA Repair DNA-Binding Proteins Doxorubicin E2F1 Transcription Factor Humans Morpholines Nuclear Proteins Promoter Regions, Genetic Protein Binding Protein Structure, Tertiary Protein-Serine-Threonine Kinases Pyrones Transcription, Genetic Tumor Suppressor Proteins Ataxia telangiectasia Moiola, Cristian Pablo De Luca, Paola Vázquez, Elba Susana De Siervi, Adriana Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription
topic_facet	ATM BRCA1 DNA damage Prostate cancer Transcription 2 morpholino 6 (1 thianthrenyl) 4 pyranone ATM protein BRCA1 associated ring domain protein 1 C terminal interacting protein doxorubicin etoposide histone H2AX methotrexate mitoxantrone protein transcription factor E2F1 unclassified drug article binding site cancer cell culture chromatin controlled study DNA damage genetic transcription human human cell male positive feedback priority journal promoter region prostate cancer protein binding protein expression protein phosphorylation protein secretion transcription regulation Antibiotics, Antineoplastic BRCA1 Protein Carrier Proteins Cell Cycle Proteins Cell Line, Tumor DNA Damage DNA Repair DNA-Binding Proteins Doxorubicin E2F1 Transcription Factor Humans Morpholines Nuclear Proteins Promoter Regions, Genetic Protein Binding Protein Structure, Tertiary Protein-Serine-Threonine Kinases Pyrones Transcription, Genetic Tumor Suppressor Proteins Ataxia telangiectasia
description	Chromosomal instability is a key feature in cancer progression. Recently we have reported that BRCA1 regulates the transcription of several genes in prostate cancer, including ATM (ataxia telangiectasia mutated). Although it is well accepted that ATM is a pivotal mediator in genotoxic stress, it is unknown whether ATM transcription is regulated during the molecular response to DNA damage. Here we investigate ATM transcription regulation in human prostate tumor PC3 cell line. We have found that doxorubicin and mitoxantrone repress ATM transcription in PC3 cells but etoposide and methotrexate do not affect ATM expression. We have demonstrated that BRCA1 binds to ATM promoter and after doxorubicin exposure, it is released. BRCA1 overexpression increases ATM transcription and this enhancement is abolished by BRCA1 depletion. Moreover, BRCA1-BRCT domain loss impairs the ability of BRCA1 to regulate ATM promoter activity, strongly suggesting that BRCT domain is essential for ATM regulation by BRCA1. BRCA1-overexpressing PC3 cells exposed to KU55933 ATM kinase inhibitor showed significant decreased ATM promoter activity compared to untreated cells, suggesting that ATM transcriptional regulation by BRCA1 is partially mediated by the ATM kinase activity. In addition, we have demonstrated E2F1 binding to ATM promoter before and after doxorubicin exposure. E2F1 overexpression diminishes ATM transcription after doxorubicin exposure which is impaired by E2F1 dominant negative mutants. Finally, the co-regulator of transcription CtIP increases ATM transcription. CtIP increases ATM transcription. Altogether, BRCA1/E2F1/CtIP binding to ATM promoter activates ATM transcription. Doxorubicin exposure releases BRCA1 and CtIP from ATM promoter still keeping E2F1 recruited and, in turn, represses ATM expression. Copyright © 2012 S. Karger AG, Basel.
author	Moiola, Cristian Pablo De Luca, Paola Vázquez, Elba Susana De Siervi, Adriana
author_facet	Moiola, Cristian Pablo De Luca, Paola Vázquez, Elba Susana De Siervi, Adriana
author_sort	Moiola, Cristian Pablo
title	Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription
title_short	Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription
title_full	Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription
title_fullStr	Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription
title_full_unstemmed	Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription
title_sort	dynamic coregulatory complex containing brca1, e2f1 and ctip controls atm transcription
publishDate	2012
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_10158987_v30_n3_p596_Moiola http://hdl.handle.net/20.500.12110/paper_10158987_v30_n3_p596_Moiola
work_keys_str_mv	AT moiolacristianpablo dynamiccoregulatorycomplexcontainingbrca1e2f1andctipcontrolsatmtranscription AT delucapaola dynamiccoregulatorycomplexcontainingbrca1e2f1andctipcontrolsatmtranscription AT vazquezelbasusana dynamiccoregulatorycomplexcontainingbrca1e2f1andctipcontrolsatmtranscription AT desierviadriana dynamiccoregulatorycomplexcontainingbrca1e2f1andctipcontrolsatmtranscription
_version_	1768542655046746112

Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription

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