Heat-induced SIRT1-mediated H4K16ac deacetylation impairs resection and SMARCAD1 recruitment to double strand breaks

Area of Science:

• Epigenetics
• Molecular Biology
• Genetics

Background:

• Hyperthermia is known to inhibit DNA double-strand break (DSB) repair via homologous recombination (HR), but the underlying mechanisms are not fully understood.
• Epigenetic modifications, such as histone acetylation, play crucial roles in maintaining genome stability and regulating DNA repair pathways.

Purpose of the Study:

• To elucidate the molecular mechanisms by which hyperthermia inhibits homologous recombination (HR) DNA repair.
• To investigate the role of histone modifications, specifically H4K16 acetylation, in hyperthermia-induced impairment of DSB repair.

Main Methods:

• Investigated the effect of hyperthermia on H4K16 acetylation levels in human, Drosophila, and yeast cells.
• Examined the recruitment of histone deacetylases, particularly SIRT1, to chromatin following heat shock.
• Assessed the impact of SMARCAD1 depletion and hyperthermia on DNA end resection, replication stress, and repair protein recruitment, including γ-H2AX.

Main Results:

• Hyperthermia was found to decrease H4K16 acetylation in a highly conserved manner across species.
• SIRT1 was identified as the primary histone deacetylase enriched at gene-rich regions upon heat shock.
• Depletion of SMARCAD1 antagonized heat-induced SIRT1 recruitment, and both SMARCAD1 depletion and hyperthermia impaired DNA end resection and increased replication stress, affecting DSB repair processing.

Conclusions:

• Hyperthermia negatively impacts chromatin organization by reducing H4K16 acetylation, mediated by SIRT1 recruitment.
• This epigenetic alteration impairs the homologous recombination (HR) pathway for DNA double-strand break (DSB) repair.
• The findings reveal a novel mechanism linking hyperthermia, chromatin regulation, and genome instability.