DAXX-ATRX regulation of p53 chromatin binding and DNA damage response

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• DAXX and ATRX are tumor suppressors involved in the histone H3.3 chaperone complex.
• Mutations in DAXX and ATRX are common in cancers exhibiting alternative lengthening of telomeres (ALT).

Purpose of the Study:

• To investigate the impact of DAXX and ATRX loss on p53 function in ALT-like cells.
• To explore the relationship between histone composition, chromatin accessibility, and p53's tumor suppressor activity.

Main Methods:

• Utilized DAXX and ATRX knock-out (KO) U87-T cells with ALT-like features.
• Performed RNA-seq, ChIP-seq, and ATAC-seq analyses.
• Assessed p53 chromatin binding, DNA damage response, and histone H3.3 levels.

Main Results:

• DAXX/ATRX KO cells showed defective p53 chromatin binding and DNA damage response.
• RNA-seq identified the p53 pathway as significantly perturbed.
• ChIP-seq and ATAC-seq revealed reduced p53 binding and chromatin accessibility at p53 response elements.
• Histone H3.3 depletion and γH2AX accumulation were observed at p53 sites in null cells.

Conclusions:

• Loss of DAXX or ATRX compromises p53 chromatin binding and DNA damage response in ALT-like cells.
• This highlights a crucial link between histone modifications, chromatin structure, and p53's role in suppressing tumors.