p53-dependent DNA repair during the DNA damage response requires actin nucleation by JMY

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• The tumor suppressor p53 is a nuclear transcription factor vital for cellular responses to DNA damage, including cell cycle arrest, apoptosis, and DNA repair.
• JMY is an actin nucleator and DNA damage-responsive protein that accumulates in the nucleus under stress.

Purpose of the Study:

• To investigate the role of nuclear JMY in transcriptional regulation during the DNA damage response.
• To identify JMY-mediated gene expression changes and its impact on DNA repair pathways.

Main Methods:

• Transcriptomics was employed to analyze gene expression changes.
• JMY depletion and knockout models were used to assess its function.
• Studies were conducted on human patient samples and cell lines.

Main Results:

• JMY is essential for regulating key p53 target genes involved in DNA repair (e.g., XPC, XRCC5, TP53I3).
• JMY depletion or knockout results in increased DNA damage and reduced cell survival.
• Nuclear JMY utilizes its Arp2/3-dependent actin nucleation for DNA lesion clearance.
• Lack of JMY correlates with higher tumor mutation counts in patients and increased sensitivity to DNA damage response kinase inhibitors.

Conclusions:

• JMY facilitates p53-dependent DNA repair under genotoxic stress.
• Actin nucleation by JMY plays a role in nuclear activity during DNA damage response.
• JMY is a critical mediator of cellular defense against DNA damage.