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Published on: November 5, 2012
Phosphorylation of Histone H4T80 Triggers DNA Damage Checkpoint Recovery
Gonzalo Millan-Zambrano1, Helena Santos-Rosa1, Fabio Puddu2
1The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Abstract:
In response to genotoxic stress, cells activate a signaling cascade known as the DNA damage checkpoint (DDC) that leads to a temporary cell cycle arrest and activation of DNA repair mechanisms. Because persistent DDC activation compromises cell viability, this process must be tightly regulated. However, despite its importance, the mechanisms regulating DDC recovery are not completely understood. Here, we identify a DNA-damage-regulated histone modification in Saccharomyces cerevisiae, phosphorylation of H4 threonine 80 (H4T80ph), and show that it triggers checkpoint inactivation. H4T80ph is critical for cell survival to DNA damage, and its absence causes impaired DDC recovery and persistent cell cycle arrest. We show that, in response to genotoxic stress, p21-activated kinase Cla4 phosphorylates H4T80 to recruit Rtt107 to sites of DNA damage. Rtt107 displaces the checkpoint adaptor Rad9, thereby interrupting the checkpoint-signaling cascade. Collectively, our results indicate that H4T80ph regulates DDC recovery.
Insights
Scientists discovered a new way cells recover from DNA damage. A specific histone modification, H4T80ph, is key for the DNA damage checkpoint (DDC) to turn off, preventing cell death.
Area of Science:
- Cellular biology
- Molecular genetics
- Biochemistry
Background:
- The DNA damage checkpoint (DDC) is crucial for cell survival following genotoxic stress.
- Efficient regulation of DDC recovery is essential to prevent cell death, but the underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the mechanisms regulating DNA damage checkpoint recovery.
- To identify novel factors involved in the inactivation of the DDC.
Main Methods:
- Utilized Saccharomyces cerevisiae as a model organism.
- Investigated histone modifications in response to genotoxic stress.
- Employed biochemical assays to study protein interactions and localization.
Main Results:
- Identified H4T80ph (phosphorylation of H4 threonine 80) as a DNA-damage-regulated histone modification.
- Demonstrated that H4T80ph triggers DDC inactivation and is critical for cell survival.
- Showed that Cla4 phosphorylates H4T80, recruiting Rtt107 to DNA damage sites, which displaces Rad9 and interrupts DDC signaling.
Conclusions:
- H4T80ph is a key regulator of DDC recovery in Saccharomyces cerevisiae.
- The H4T80ph-Cla4-Rtt107 pathway is essential for timely checkpoint inactivation and cell survival.
- This study elucidates a novel mechanism controlling the resolution of DNA damage responses.
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