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Marks to stop the clock: histone modifications and checkpoint regulation in the DNA damage response
Stephen E Humpal1, David A Robinson, Jocelyn E Krebs
1Department of Biological Sciences, University of Alaska-Anchorage, 3211 Providence Drive, Anchorage, AK99508, USA.
Abstract:
DNA damage from endogenous and exogenous sources occurs throughout the cell cycle. In response to this damage, cells have developed a series of biochemical responses that allow them to recover from DNA damage and prevent mutations from being passed on to daughter cells. An important part of the DNA damage response is the ability to halt the progression of the cell cycle, allowing damaged DNA to be repaired. The cell cycle can be halted at semi-discrete times, called checkpoints, which occur at critical stages during the cell cycle. Recent work in our laboratory and by others has shown the importance of post-translational histone modifications in the DNA damage response. While many histone modifications have been identified that appear to facilitate repair per se, there have been surprisingly few links between these modifications and DNA damage checkpoints. Here, we review how modifications to histone H2A serine 129 (HSA129) and histone H3 lysine 79 (H3K79) contribute to the stimulation of the G1/S checkpoint. We also discuss recent findings that conflict with the current model of the way methylated H3K79 interacts with the checkpoint adaptor protein Rad9.
Insights
Cellular DNA damage triggers responses to prevent mutations. This review highlights how histone modifications, specifically HSA129 and H3K79, are crucial for activating cell cycle checkpoints, ensuring DNA repair before cell division.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Cells possess intricate DNA damage response (DDR) mechanisms to maintain genomic stability.
- The cell cycle progression is tightly regulated by checkpoints that halt division upon DNA damage.
- Post-translational histone modifications are increasingly recognized as key regulators in DDR.
Purpose of the Study:
- To review the role of specific histone modifications in DNA damage checkpoints.
- To elucidate the contribution of histone H2A serine 129 (HSA129) and histone H3 lysine 79 (H3K79) to checkpoint activation.
- To discuss current models and conflicting data regarding H3K79 methylation and checkpoint proteins.
Main Methods:
- Literature review of studies on DNA damage response pathways.
- Analysis of research on post-translational histone modifications, focusing on HSA129 and H3K79.
- Examination of experimental data linking histone modifications to cell cycle checkpoints.
Main Results:
- HSA129 and H3K79 modifications are critical for stimulating the G1/S cell cycle checkpoint.
- These histone modifications facilitate the DNA damage response by halting cell cycle progression.
- Emerging data challenges existing models of methylated H3K79 interaction with Rad9.
Conclusions:
- Histone modifications, particularly HSA129 and H3K79, play a vital role in DNA damage checkpoint activation.
- Understanding these modifications provides insights into maintaining genome integrity.
- Further research is needed to fully clarify the mechanisms of H3K79 methylation in checkpoint control.
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