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Diverse roles for histone H2A modifications in DNA damage response pathways in yeast
John D Moore1, Oya Yazgan, Yeganeh Ataian
1Department of Biological Sciences, University of Alaska, Anchorage, Alaska 99508, USA.
Abstract:
There are many types of DNA damage that are repaired by a multiplicity of different repair pathways. All damage and repair occur in the context of chromatin, and histone modifications are involved in many repair processes. We have analyzed the roles of H2A and its modifications in repair by mutagenizing modifiable residues in the N- and C-terminal tails of yeast H2A and by testing strains containing these mutations in multiple DNA repair assays. We show that residues in both tails are important for homologous recombination and nonhomologous end-joining pathways of double-strand break repair, as well as for survival of UV irradiation and oxidative damage. We show that H2A serine 122 is important for repair and/or survival in each of these assays. We also observe a complex pattern of H2A phosphorylation at residues S122, T126, and S129 in response to different damage conditions. We find that overlapping but nonidentical groups of H2A residues in both tails are involved in different pathways of repair. These data suggest the presence of a set of H2A "damage codes" in which distinct patterns of modifications on both tails of H2A may be used to identify specific types of damage or to promote specific repair pathways.
Insights
Histone H2A modifications in yeast are crucial for DNA repair pathways. Specific patterns of H2A tail modifications act as "damage codes" to direct repair processes for various DNA lesions.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- DNA damage is repaired by multiple pathways within the chromatin context.
- Histone modifications play a role in DNA repair processes.
Purpose of the Study:
- To investigate the role of histone H2A modifications in DNA repair pathways.
- To identify specific H2A residues and their modifications involved in repair.
Main Methods:
- Mutagenesis of modifiable residues in yeast H2A N- and C-terminal tails.
- Assessing mutant strains in DNA repair assays (homologous recombination, nonhomologous end-joining, UV, oxidative damage).
- Analyzing H2A phosphorylation patterns.
Main Results:
- H2A tail residues are essential for double-strand break repair (homologous recombination and nonhomologous end-joining) and survival from UV/oxidative damage.
- H2A serine 122 is critical for repair and survival across multiple assays.
- Distinct patterns of H2A phosphorylation at S122, T126, and S129 were observed under different damage conditions.
- Overlapping but non-identical H2A residue groups participate in different repair pathways.
Conclusions:
- H2A tail modifications function as "damage codes" to signal specific DNA damage types.
- These codes may direct the recruitment or activity of specific DNA repair pathways.
- Histone H2A acts as a central regulator in the DNA damage response.
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