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c-Myc accelerates S-phase and requires WRN to avoid replication stress
Kristin Robinson1, Nichaya Asawachaicharn, Denise A Galloway
1Program in Cancer Biology and Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Plos One
|June 26, 2009
Summary
Overexpressed c-Myc accelerates DNA replication, causing damage that Werner DNA helicase (WRN) normally repairs. Without WRN, c-Myc-driven cells rapidly senesce, revealing a potential cancer therapy target.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- c-Myc is known to regulate DNA replication.
- The impact of c-Myc on cell cycle dynamics and replication-associated DNA damage remains unclear.
Purpose of the Study:
- To investigate the role of c-Myc in regulating DNA replication and its consequences on cell cycle progression and DNA damage.
- To elucidate the involvement of Werner DNA helicase (WRN) in c-Myc-mediated DNA replication and subsequent cellular responses.
Main Methods:
- Overexpression and deficiency models of c-Myc in primary human fibroblasts.
- Depletion of Werner DNA helicase (WRN) in c-Myc overexpressing cells.
- Analysis of S-phase duration, DNA synthesis sites, and DNA damage markers.
- Investigation of the replication stress pathway (ATR, CHK1, CHK2, p53) and senescence induction.
- Assessment of p53's role in rescuing senescence.
Main Results:
- c-Myc overexpression accelerates S-phase, while c-Myc deficiency prolongs it.
- Depletion of WRN in c-Myc overexpressing cells significantly increases DNA damage at replication sites.
- This damage activates the ATR/CHK1/CHK2/p53 replication stress pathway, leading to rapid senescence.
- Depletion of p53 prevents senescence in WRN-deficient, c-Myc-overexpressing cells.
Conclusions:
- WRN is crucial for repairing replication abnormalities induced by c-Myc-accelerated DNA synthesis.
- This study offers a mechanistic explanation for c-Myc-induced DNA damage and senescence.
- c-Myc overexpressing cells exhibit a vulnerability related to WRN function, potentially exploitable in cancer therapy.
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