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Quantifying Replication Stress in Ovarian Cancer Cells Using Single-Stranded DNA Immunofluorescence
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Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication
Jingkun Zeng1, Stephanie A Hills1, Eiko Ozono1
1Chromosome Replication Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
Cell
|January 21, 2023
Summary
The p53 tumor suppressor can paradoxically promote whole-genome duplication (WGD) in cancer. Elevated cyclin E1 expression, facilitated by p53, drives endoreduplication and cancer evolution.
Area of Science:
- Cancer Biology
- Genetics
- Cellular Biology
Background:
- Whole-genome duplication (WGD) is a common event in cancer, driving aneuploidy.
- The tumor suppressor p53's role in WGD is complex, acting as both a barrier and a facilitator.
- WGD in wild-type p53 tumors often involves E2F pathway activation and CCNE1 amplification.
Purpose of the Study:
- To elucidate the role of p53 in promoting WGD via endoreduplication.
- To investigate the mechanism by which elevated cyclin E1 contributes to WGD.
- To understand how p53 influences cell cycle progression following mitotic bypass.
Main Methods:
- Analysis of cell cycle regulation in the context of elevated cyclin E1 expression.
- Investigating the involvement of ATR, Chk1, p21, Wee1, and APC/CCdh1 in WGD.
- Studying the impact of cyclin E1 on p53-mediated senescence after mitotic bypass.
Main Results:
- Elevated cyclin E1 induces replicative stress and G2 arrest via ATR/Chk1.
- p53, p21, and Wee1 cooperate to inhibit CDK activity, promoting APC/CCdh1 activation and mitotic bypass.
- Cyclin E1 suppresses p53-dependent senescence, enabling completion of endoreduplication.
Conclusions:
- p53 can promote WGD by facilitating endoreduplication, contributing to cancer evolution.
- The interplay between cyclin E1, p53, and cell cycle regulators is crucial for WGD.
- Targeting this pathway could offer new therapeutic strategies for WGD-driven cancers.
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