Beyond ATM: the protein kinase landscape of the DNA damage response

Area of Science:

• Molecular Biology
• Cellular Signaling
• Genomics

Background:

• DNA is continuously exposed to damaging agents, leading to lesions like double-strand breaks (DSBs).
• The DNA damage response (DDR) is a critical cellular network activated by DSBs, primarily initiated by ATM protein kinase.
• ATM kinase phosphorylates key proteins, orchestrating various branches of the DDR.

Purpose of the Study:

• To review the involvement of numerous protein kinases in the DDR beyond direct ATM substrates.
• To explore the expanded landscape of protein phosphorylation in DNA damage signaling.
• To understand the role of protein phosphorylation in maintaining genomic stability.

Main Methods:

• Analysis of phosphoproteomic screens to identify damage-induced phosphorylations.
• Review of evidence from specific pathway documentation.
• Integration of data from high-throughput screening approaches.

Main Results:

• Identified numerous protein kinases, in addition to ATM, involved in the DDR.
• Demonstrated that protein phosphorylation plays a broader role in DDR than previously understood.
• Revealed an extensive signaling network with cross-talk between diverse protein kinases.

Conclusions:

• The DDR involves a complex, interlaced network of protein kinases, extending beyond ATM.
• Protein phosphorylation is a versatile modification critical for genomic stability maintenance.
• The DDR represents one of the most extensive signaling responses to cellular stimuli.