BMI1 reduces ATR activation and signalling caused by hydroxyurea
Xiaozeng Lin1,2,3, Fengxiang Wei1,2,3,4, Peter Whyte5
1Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Oncotarget
|November 23, 2017
Summary
BMI1 protein plays a role in DNA damage response by reducing ATR activation, which is crucial for cell cycle checkpoints. This finding reveals BMI1
Area of Science:
- Cellular Biology
- Molecular Biology
- Genetics
Background:
- BMI1 is known to facilitate DNA damage response (DDR) to double-strand breaks.
- Its role in DDR initiated by single-strand DNA (ssDNA) lesions is not well understood.
Purpose of the Study:
- To investigate the function of BMI1 in the DDR pathway activated by ssDNA lesions.
- To determine BMI1's effect on ATR activation and S-phase checkpoints.
Main Methods:
- Hydroxyurea (HU) was used to induce ssDNA lesions in MCF7 and DU145 cells.
- BMI1 overexpression and knockdown were performed.
- Levels of ATR activation, H2AX phosphorylation (γH2AX), CHK1 phosphorylation (CHK1pS345), CDK1 phosphorylation (CDK1pY15), and S-phase arrest were assessed.
- BMI1 protein interactions with TOPBP1 and ATR were analyzed using various BMI1 mutants.
Main Results:
- BMI1 overexpression reduced HU-induced ATR activation, γH2AX, CHK1pS345, CDK1pY15, and S-phase arrest.
- BMI1 knockdown enhanced these events.
- BMI1 interacts with both TOPBP1 and ATR.
- Specific structural domains of BMI1 were not essential for its inhibitory effect on ATR-mediated CHK1pS345.
Conclusions:
- BMI1 attenuates ATR activation in response to ssDNA damage.
- BMI1 may decrease ATR activation by binding to TOPBP1 and/or ATR.
- This study elucidates a novel role for BMI1 in regulating the S-phase checkpoint via the ATR pathway.
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