JMJD6 modulates DNA damage response through downregulating H4K16ac independently of its enzymatic activity

Area of Science:

• Epigenetics
• Molecular Biology
• Cellular Biology

Background:

• DNA damage response (DDR) is crucial for maintaining genomic stability.
• Chromatin modifications and structure play vital roles in DDR signaling.
• The precise mechanisms confining chromatin alterations to DNA lesions by epigenetic factors are not fully understood.

Purpose of the Study:

• To investigate the role of JMJD6 in the DNA damage response.
• To elucidate the function of JMJD6 in epigenetic regulation at DNA lesions.
• To understand how JMJD6 influences DNA repair pathways and cell survival.

Main Methods:

• Microirradiation to induce DNA double-strand breaks (DSBs).
• Recruitment assays for JMJD6 to DSBs.
• Analysis of histone ubiquitination and repair protein accumulation.
• Assessment of nonhomologous end joining (NHEJ) and homologous recombination (HR) efficiency.
• Cell-cycle checkpoint recovery and cell survival assays.
• Co-immunoprecipitation to study protein interactions (JMJD6 and SIRT1).
• Western blotting to detect histone acetylation (H4K16ac).

Main Results:

• JMJD6 is recruited to DSBs and controls the spreading of histone ubiquitination and transcriptional silencing.
• JMJD6 does not regulate the initial DNA damage sensing.
• JMJD6 deficiency promotes NHEJ and HR efficiency, accelerates checkpoint recovery, and enhances cell survival after irradiation.
• JMJD6 interacts with SIRT1, recruiting it to chromatin to downregulate H4K16ac around DSBs, independent of its catalytic activity.

Conclusions:

• JMJD6 acts as a critical epigenetic modulator at DNA lesions.
• JMJD6 regulates the extent of chromatin alterations and influences DNA repair outcomes.
• The findings expand the understanding of epigenetic factors in orchestrating the DNA damage response and cellular recovery.