The mammalian UV response: mechanism of DNA damage induced gene expression

Area of Science:

• Cellular biology
• Molecular biology
• Signal transduction

Background:

• DNA damage triggers cellular responses, including transcription factor activation.
• Early nuclear events involve post-translational modification of AP-1 (c-Jun/c-Fos).
• Extranuclear signaling components like Src, Ras, Raf-1, and MAP-2 kinase are crucial.

Purpose of the Study:

• To investigate the signaling pathway initiated by DNA damage.
• To determine if DNA damage or its secondary effects generate the signal for transcription factors.
• To explore the existence and nature of reverse signaling from nucleus to cell surface.

Main Methods:

• Treatment of cultured mammalian cells with DNA damaging agents.
• Analysis of early nuclear events, including AP-1 modification.
• Investigation of extranuclear signal transduction pathways.
• Experimental interruption of UV-induced signaling at the cell surface.

Main Results:

• DNA damage rapidly activates transcription factors and stabilizes p53.
• Early nuclear events (e.g., AP-1 modification) require extranuclear signaling components.
• A reverse signaling pathway from the nucleus to the cell surface may exist.
• UV-induced signaling converges with pathways activated by phorbol esters and growth factors.

Conclusions:

• Cellular responses to DNA damage involve complex signaling networks.
• Both extranuclear and potentially intranuclear-to-extranuclear signaling pathways are involved.
• Understanding these pathways is critical for comprehending cellular responses to genotoxic stress.