- Ataxia-telangiectasia (A-T) is a neurodegenerative disease caused by a mutation of the A-T mutated (ATM) gene
- ATM encodes a serine/threonine protein kinase of the phosphatidylinositol-3 kinase-related kinase (PIKK) family. ATM is responsible for activating cell cycle checkpoints that arrest the cell cycle until DNA repair is complete. Individuals with A-T are thus more likely to contract cancer. ATM also protects neurons from degeneration and is required for neuronal vesicle trafficking. It is also required for maintaining histone deacetylase 4 (HDAC4) in the cytoplasm.
- Histone deacetylase is a protein that removes the acetyl group from histone, allowing the histone to wrap DNA more tightly
- The serine/threonine protein kinase is a kinase enzyme that phosphorylates the OH group of serine or threonine (see amino acids here)
- Polycomb group (PcG) family proteins are transcriptional repressors that epigenetically modify chromatin and participate in the establishment and maintenance of many cell fates. PcG proteins are involved in stem cell self-renewal and tumorigenesis, the production or formation of a tumor. Mammals have two polycomb protein complexis, PRC1 and PRC2. PRC2 consists of EZH2 (enhancer of zeste homolog 2), SUZ12 (suppressor of zeste 12) and EED (embryonic ectoderm development).
- EZH2 catalyzes the addition of methyl groups to histone H3 at Lys27 (H3K27) leading to epigenetic silencing. EZH2 plays a role in X-chromosome inactivation and is overexpressed in solid tumors and is implicated in tumor progression. EZH2 interacts with cyclin-dependent kinase-1 (CDK1) to control self-renewal or differentiation. Knockdown of EZH2 leads to decreased proliferation of cancer cells.
- In the of cerebella of A-T patients in an A-T mouse models, the levels of H3K27 trimethylation are elevated as a result of the loss of ATM-dependent EZH2 phosphorylation. This phosphorylation normally destabilizes EZH2, thus reducing its assocation with the PRC2 complex and reducing subsequent H3K27 methylation.
Li, Jiali, et al. "EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia." Nature neuroscience 16.12 (2013): 1745-1753.Share