Loss of MED12 activates the TGFß pathway to promote chemoresistance and replication fork stability in BRCA-deficient cells.
Nucleic Acids Res
; 49(22): 12855-12869, 2021 12 16.
Article
em En
| MEDLINE
| ID: mdl-34871431
ABSTRACT
Understanding chemoresistance mechanisms in BRCA-deficient cells will allow for identification of biomarkers for predicting tumor response to therapy, as well as the design of novel therapeutic approaches targeting this chemoresistance. Here, we show that the protein MED12, a component of the Mediator transcription regulation complex, plays an unexpected role in regulating chemosensitivity in BRCA-deficient cells. We found that loss of MED12 confers resistance to cisplatin and PARP inhibitors in both BRCA1- and BRCA2-deficient cells, which is associated with restoration of both homologous recombination and replication fork stability. Surprisingly, MED12-controlled chemosensitivity does not involve a function of the Mediator complex, but instead reflects a distinct role of MED12 in suppression of the TGFß pathway. Importantly, we show that ectopic activation of the TGFß pathway is enough to overcome the fork protection and DNA repair defects of BRCA-mutant cells, resulting in chemoresistance. Our work identifies the MED12-TGFß module as an important regulator of genomic stability and chemosensitivity in BRCA-deficient cells.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta
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Resistencia a Medicamentos Antineoplásicos
/
Proteína BRCA1
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Proteína BRCA2
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Replicação do DNA
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Complexo Mediador
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Nucleic Acids Res
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos