Title: Loss of MED12 activates the TGFβ pathway to promote chemoresistance and replication fork stability in BRCA-deficient cells.
Authors: Jackson, Lindsey M; Dhoonmoon, Ashna; Hale, Anastasia; Dennis, Kady A; Schleicher, Emily M; Nicolae, Claudia M; Moldovan, George-Lucian
Published In Nucleic Acids Res, (2021 12 16)
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 TGFβ pathway. Importantly, we show that ectopic activation of the TGFβ pathway is enough to overcome the fork protection and DNA repair defects of BRCA-mutant cells, resulting in chemoresistance. Our work identifies the MED12-TGFβ module as an important regulator of genomic stability and chemosensitivity in BRCA-deficient cells.
PubMed ID: 34871431
MeSH Terms: Antineoplastic Agents/pharmacology; BRCA1 Protein/deficiency; BRCA1 Protein/genetics*; BRCA1 Protein/metabolism; BRCA2 Protein/deficiency; BRCA2 Protein/genetics*; BRCA2 Protein/metabolism; Cell Line; Cell Line, Tumor; Cell Survival/drug effects; Cell Survival/genetics; Cisplatin/pharmacology; DNA Repair; DNA Replication/genetics*; DNA/chemistry; DNA/genetics; DNA/metabolism; Drug Resistance, Neoplasm/genetics*; HeLa Cells; Humans; Mediator Complex/genetics*; Mediator Complex/metabolism; Phthalazines/pharmacology; Piperazines/pharmacology; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology; RNA Interference; Signal Transduction/genetics; Transforming Growth Factor beta/genetics*; Transforming Growth Factor beta/metabolism