Acetyltransferase p300 regulates NBS1-mediated DNA damage response

Area of Science:

• Molecular Biology
• Cellular Biology
• Biochemistry

Background:

• The precise role of p300 in DNA damage response pathways remains largely undefined.
• Understanding how ATM-mediated phosphorylation impacts p300 function is critical for elucidating DNA repair mechanisms.

Purpose of the Study:

• To investigate the functional consequences of ATM-dependent phosphorylation of p300 on DNA damage response.
• To determine the role of p300 phosphorylation at serine 106 (S106) in regulating NBS1 stability and DNA damage site recruitment.

Main Methods:

• Utilized non-phosphorylatable p300 mutants (S106A) to assess the impact of phosphorylation.
• Employed dominant-negative p300 variants lacking enzymatic activity.
• Analyzed NBS1 protein stability, NBS1-p300 interactions, and NBS1 recruitment to damaged DNA sites.

Main Results:

• Phosphorylation of p300 at S106 by ATM is essential for maintaining NBS1 stability.
• A non-phosphorylatable S106A p300 mutant destabilized NBS1 and reduced NBS1-p300 complex formation.
• NBS1 recruitment to damaged DNA was significantly impaired in the presence of S106A p300.
• p300's acetyltransferase activity is necessary for NBS1 stability.

Conclusions:

• ATM-mediated phosphorylation of p300 plays a regulatory role in NBS1-dependent DNA damage response.
• These regulatory events are contingent upon p300's acetylation activity.
• p300 phosphorylation influences DNA repair through modulation of NBS1 stability and localization.