Sp1 phosphorylation by ATM downregulates BER and promotes cell elimination in response to persistent DNA damage

Area of Science:

• Molecular Biology
• Cellular Biology
• Genetics

Background:

• The ataxia-telangiectasia mutated (ATM) protein is vital for DNA quality control and cell cycle regulation following DNA damage.
• ATM activation typically facilitates DNA repair, but its role in ATM-dependent cell death due to persistent DNA damage is not fully understood.

Purpose of the Study:

• To elucidate the mechanisms by which ATM induces cell death in response to persistent DNA strand breaks.
• To identify the molecular players involved in ATM-mediated apoptosis and DNA damage aggravation.

Main Methods:

• Investigated ATM's interaction with transcription factor Sp1 upon DNA damage.
• Analyzed the impact of Sp1 phosphorylation and degradation on DNA repair gene expression.
• Assessed the downstream effects on apoptosis and cell susceptibility to elimination.

Main Results:

• ATM phosphorylates and triggers the degradation of transcription factor Sp1 when DNA strand breaks persist.
• Sp1 is crucial for regulating the expression of the base excision repair gene XRCC1.
• Sp1 degradation leads to suppressed DNA repair, increased DNA damage, and activation of pro-apoptotic genes.

Conclusions:

• ATM acts as a 'gatekeeper' by detecting persistent DNA damage through Sp1 degradation.
• This mechanism initiates a feedback loop that compromises DNA repair and promotes cell elimination via apoptosis and NK cells.
• Uncovers a novel pathway linking DNA damage detection, repair suppression, and programmed cell death.