Combined Interactions of Plant Homeodomain and Chromodomain Regulate NuA4 Activity at DNA Double-Strand Breaks
| Autor: | Li Chiao Chia, Wei Sheng Wu, Po Cheng Hung, Hungjiun Liaw, Wen Bin Yang, Kyungjae Myung, Wen Pin Su, Jui Yang Lin, Song Bin Chang, Mau-Sun Chang, Yi Ju Lin, Jan Jong Hung, Sen Huei Hsu, Zong Da Jiang, Yi Cheng Chen, Min Yu Shih |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Saccharomyces cerevisiae Proteins Mutant Saccharomyces cerevisiae Investigations medicine.disease_cause Methylation Chromodomain Histones 03 medical and health sciences chemistry.chemical_compound Bleomycin Acetyltransferases Drug Resistance Fungal Genetics medicine DNA Breaks Double-Stranded DNA Fungal Histone Acetyltransferases Homeodomain Proteins Mutation Binding Sites biology Acetylation biology.organism_classification Molecular biology Chromatin 030104 developmental biology Histone chemistry biology.protein DNA |
| Zdroj: | Genetics. 202(1) |
| ISSN: | 1943-2631 |
| Popis: | DNA double-strand breaks (DSBs) represent one of the most threatening lesions to the integrity of genomes. In yeast Saccharomyces cerevisiae, NuA4, a histone acetylation complex, is recruited to DSBs, wherein it acetylates histones H2A and H4, presumably relaxing the chromatin and allowing access to repair proteins. Two subunits of NuA4, Yng2 and Eaf3, can interact in vitro with methylated H3K4 and H3K36 via their plant homeodomain (PHD) and chromodomain. However, the roles of the two domains and how they interact in a combinatorial fashion are still poorly characterized. In this study, we generated mutations in the PHD and chromodomain that disrupt their interaction with methylated H3K4 and H3K36. We demonstrate that the combined mutations in both the PHD and chromodomain impair the NuA4 recruitment, reduce H4K12 acetylation at the DSB site, and confer sensitivity to bleomycin that induces DSBs. In addition, the double mutant cells are defective in DSB repair as judged by Southern blot and exhibit prolonged activation of phospho-S129 of H2A. Cells harboring the H3K4R, H3K4R, K36R, or set1Δ set2Δ mutant that disrupts H3K4 and H3K36 methylation also show very similar phenotypes to the PHD and chromodomain double mutant. Our results suggest that multivalent interactions between the PHD, chromodomain, and methylated H3K4 and H3K36 act in a combinatorial manner to recruit NuA4 and regulate the NuA4 activity at the DSB site. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|