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Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription.
Cristian Moiola1, Paola De Luca, Javier Cotignola
1Department of Biological Chemistry, School of Sciences (FCEN), University of Buenos Aires (UBA), CONICET, Buenos Aires, Argentina.
Summary
BRCA1 regulates ATM gene transcription in prostate cancer cells. DNA damage response involves BRCA1, E2F1, and CtIP binding to the ATM promoter, with doxorubicin altering this interaction to repress ATM expression.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Chromosomal instability is a hallmark of cancer progression.
- BRCA1 (Breast cancer gene 1) is known to regulate gene transcription in prostate cancer, including ATM (ataxia telangiectasia mutated).
- ATM is a critical mediator of genotoxic stress, but its transcriptional regulation during DNA damage response is not fully understood.
Purpose of the Study:
- To investigate the regulation of ATM transcription in human prostate tumor PC3 cells.
- To elucidate the role of BRCA1 in ATM transcription following DNA damage.
- To identify other transcription factors and co-regulators involved in ATM gene expression.
Main Methods:
- Treatment of PC3 cells with DNA-damaging agents (doxorubicin, mitoxantrone, etoposide, methotrexate).
- Assessment of ATM mRNA and protein expression levels.
- Chromatin immunoprecipitation (ChIP) assays to detect BRCA1, E2F1, and CtIP binding to the ATM promoter.
- Analysis of ATM promoter activity using reporter assays.
- Investigation of the role of ATM kinase activity and BRCA1 domains (BRCT) using inhibitors and mutants.
Main Results:
- Doxorubicin and mitoxantrone repressed ATM transcription in PC3 cells; etoposide and methotrexate did not.
- BRCA1 binds to the ATM promoter and is released upon doxorubicin exposure.
- BRCA1 overexpression enhanced ATM transcription, while depletion abolished this effect.
- Loss of the BRCA1-BRCT domain impaired ATM promoter regulation.
- ATM kinase activity partially mediates BRCA1's transcriptional regulation of ATM.
- E2F1 binds to the ATM promoter, and its overexpression diminished ATM transcription post-doxorubicin exposure.
- CtIP (C-terminal-binding protein interacting protein) increased ATM transcription.
- BRCA1, E2F1, and CtIP binding activates ATM transcription; doxorubicin disrupts this by releasing BRCA1 and CtIP while retaining E2F1, leading to ATM repression.
Conclusions:
- BRCA1, E2F1, and CtIP form a complex that activates ATM transcription in prostate cancer cells.
- DNA damage, specifically doxorubicin treatment, disrupts this complex, leading to the repression of ATM transcription.
- The BRCT domain of BRCA1 and ATM kinase activity are crucial for this regulatory mechanism.
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