Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication

Area of Science:

• Cell Biology
• Cancer Research
• Genetics

Background:

• Early tumorigenesis involves the DNA-damage response (DDR).
• Oncogene activation induces cellular senescence, limiting proliferation.
• The causal link between DDR and oncogene-induced senescence (OIS) remains unclear.

Purpose of the Study:

• To investigate the causal relationship between DDR activation and OIS.
• To determine if DDR is a prerequisite for OIS.
• To elucidate the role of DNA replication in OIS.

Main Methods:

• Expression of activated H-RasV12 oncogene in human cells.
• Experimental inactivation of the DDR.
• In vivo DNA labeling and molecular DNA combing.
• Analysis of DNA replication and origin firing.

Main Results:

• OIS is a consequence of robust DDR activation following oncogene expression.
• Inactivating DDR abrogates OIS and promotes cell transformation.
• Senescent cells exhibit partly replicated DNA and multiple origin firings.
• Oncogene activation increases active replicons and alters replication fork progression.
• DDR activation by oncogenes requires DNA replication.

Conclusions:

• OIS results from DDR enforcement triggered by oncogene-induced DNA hyper-replication.
• DDR is essential for preventing oncogene-driven cell transformation.