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KSR1 is required for cell cycle reinitiation following DNA damage
Gina L Razidlo1, Heidi J Johnson, Scott M Stoeger
1Eppley Institute for the Research of Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696, USA.
The Journal of Biological Chemistry
|January 17, 2009
Summary
Kinase suppressor of Ras 1 (KSR1) is essential for cell cycle re-entry after DNA damage. KSR1 facilitates ERK signaling, enabling cells to recover from DNA interstrand cross-links.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- Kinase suppressor of Ras 1 (KSR1) acts as a scaffold protein and promotes the Raf/MEK/ERK signaling pathway.
- KSR1 is crucial for ERK activation by growth factors and certain cytotoxic agents.
Purpose of the Study:
- To investigate the role of KSR1 in cellular responses to DNA interstrand cross-linking agents.
- To determine KSR1's function in cell cycle re-initiation and proliferation following DNA damage.
Main Methods:
- Utilized KSR1 knockout cells and cells expressing mutated KSR1.
- Assessed ERK activation, cell cycle progression (G2/M arrest), and DNA damage repair (gamma-H2AX foci resolution).
- Investigated the impact of KSR1 expression and KSR1-ERK interaction on cell cycle re-initiation.
Main Results:
- KSR1 is required for maximal ERK activation induced by DNA interstrand cross-linking agents like mitomycin C (MMC).
- KSR1-deficient cells fail to recover from MMC-induced G2/M arrest, despite successful DNA damage repair.
- KSR1-ERK interaction is critical for cell cycle re-initiation following MMC treatment; constitutive ERK activation alone is insufficient.
Conclusions:
- KSR1 plays a specific and essential role in signaling for cell cycle re-initiation after DNA interstrand cross-link damage.
- KSR1-mediated ERK signaling is indispensable for cellular recovery and proliferation post-DNA damage, independent of DNA repair completion.
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