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Histone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response
Gary D Kao1, W Gillies McKenna, Matthew G Guenther
1Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. kao@xrt.upenn.edu
Abstract:
Anumber of proteins are recruited to nuclear foci upon exposure to double-strand DNA damage, including 53BP1 and Rad51, but the precise role of these DNA damage-induced foci remain unclear. Here we show in a variety of human cell lines that histone deacetylase (HDAC) 4 is recruited to foci with kinetics similar to, and colocalizes with, 53BP1 after exposure to agents causing double-stranded DNA breaks. HDAC4 foci gradually disappeared in repair-proficient cells but persisted in repair-deficient cell lines or cells irradiated with a lethal dose, suggesting that resolution of HDAC4 foci is linked to repair. Silencing of HDAC4 via RNA interference surprisingly also decreased levels of 53BP1 protein, abrogated the DNA damage-induced G2 delay, and radiosensitized HeLa cells. Our combined results suggest that HDAC4 is a critical component of the DNA damage response pathway that acts through 53BP1 and perhaps contributes in maintaining the G2 cell cycle checkpoint.
Insights
Histone deacetylase 4 (HDAC4) is recruited to DNA damage sites, colocalizing with 53BP1. Its resolution indicates successful DNA repair, and its silencing impairs the DNA damage response.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Nuclear foci form upon DNA damage, involving proteins like 53BP1 and Rad51.
- The exact function of these DNA damage-induced foci is not fully understood.
Purpose of the Study:
- To investigate the role of histone deacetylase 4 (HDAC4) in the DNA damage response.
- To determine the relationship between HDAC4 foci and DNA repair processes.
Main Methods:
- Utilized various human cell lines.
- Observed protein recruitment to nuclear foci using microscopy.
- Employed RNA interference to silence HDAC4.
- Assessed DNA damage response pathways, including G2 cell cycle delay and radiosensitivity.
Main Results:
- HDAC4 was recruited to nuclear foci with kinetics and localization similar to 53BP1 after double-strand DNA breaks.
- HDAC4 foci resolution correlated with DNA repair proficiency.
- Silencing HDAC4 reduced 53BP1 protein levels, abrogated the G2 delay, and increased radiosensitivity in HeLa cells.
Conclusions:
- HDAC4 is a crucial component of the DNA damage response pathway.
- HDAC4 acts via 53BP1 and contributes to maintaining the G2 cell cycle checkpoint.
- HDAC4 foci dynamics provide insights into DNA repair status.