MORC2mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs

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Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription.

Rafael A. Irizarry, Jef D. Boeke, Peter McCaffery … (2006)

Metabolic enzymes rarely regulate informational processes like gene expression. Yeast acetyl-CoA synthetases (Acs1p and 2p) are exceptional, as they are important not only for carbon metabolism but also are shown here to supply the acetyl-CoA for histone acetylation by histone acetyltransferases (HATs). acs2-Ts mutants exhibit global histone deacetylation, transcriptional defects, and synthetic growth defects with HAT mutants at high temperatures. In glycerol with ethanol, Acs1p is an alternate acetyl-CoA source for HATs. Rapid deacetylation after Acs2p inactivation suggests nuclear acetyl-CoA synthesis is rate limiting for histone acetylation. Different histone lysines exhibit distinct deacetylation rates, with N-terminal tail lysines deacetylated rapidly and H3 lysine 56 slowly. Yeast mitochondrial and nucleocytosolic acetyl-CoA pools are biochemically isolated. Thus, acetyl-CoA metabolism is directly linked to chromatin regulation and may affect diverse cellular processes in which acetylation and metabolism intersect, such as disease states and aging.

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Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia-telangiectasia

Jiali Li, Jianmin Chen, Christopher L. Ricupero … (2012)

Ataxia-telangiectasia (A-T) is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ATM-deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin as well as to MEF2A and CREB, leading to histone de-acetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts the neurodegenerative changes and rescues several behavioral abnormalities of Atm mutants. Full rescue, however, also requires HDAC4 in the cytoplasm, suggesting that the A-T phenotype results both from a loss of cytoplasmic HDAC4 and its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The HDAC4 phosphatase, PP2A, is down regulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and nuclear accumulation. Our results define a crucial role of nuclear accumulation and cytoplasmic depletion of HDAC4 in the events leading to A-T neurodegeneration.

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MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response.

Qiang Li, Arathy D. S. Nair, Kazufumi Ohshiro … (2012)

Chromatin dynamics play a central role in maintaining genome integrity, but how this is achieved remains largely unknown. Here, we report that microrchidia CW-type zinc finger 2 (MORC2), an uncharacterized protein with a derived PHD finger domain and a conserved GHKL-type ATPase module, is a physiological substrate of p21-activated kinase 1 (PAK1), an important integrator of extracellular signals and nuclear processes. Following DNA damage, MORC2 is phosphorylated on serine 739 in a PAK1-dependent manner, and phosphorylated MORC2 regulates its DNA-dependent ATPase activity to facilitate chromatin remodeling. Moreover, MORC2 associates with chromatin and promotes gamma-H2AX induction in a PAK1 phosphorylation-dependent manner. Consequently, cells expressing MORC2-S739A mutation displayed a reduction in DNA repair efficiency and were hypersensitive to DNA-damaging agent. These findings suggest that the PAK1-MORC2 axis is critical for orchestrating the interplay between chromatin dynamics and the maintenance of genomic integrity through sequentially integrating multiple essential enzymatic processes. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.