MYST family lysine acetyltransferase facilitates Ataxia Telangiectasia Mutated (ATM) kinase-mediated DNA damage response in Toxoplasma gondii

Abstract

The MYST family of lysine acetyltransferases (KATs) function in a wide variety of cellular operations, including gene regulation and theDNAdamage response. Here we report the characterization of the second MYST family KAT in the protozoan parasite Toxoplasma gondii (TgMYST-B). Toxoplasma causes birth defects and is an opportunistic pathogen in the immuno-compromised, the latter due to its ability to convert into a latent cyst (bradyzoite). We demonstrate that TgMYST-B can gain access to the parasite nucleus and acetylate histones. Overexpression of recombinant, tagged TgMYST-B reduces growth rate in vitro and confers protection from a DNA-alkylating agent. Expression of mutant TgMYST-B produced no growth defect and failed to protect against DNA damage. We demonstrate that cells overexpressing TgMYST-B have increased levels of ataxia telangiectasia mutated (ATM) kinase and phosphorylated H2AX and that TgMYST-B localizes to the ATM kinase gene. Pharmacological inhibitors of ATM kinase or KATs reverse the slow growth phenotype seen in parasites overexpressing TgMYST-B. These studies are the first to show that a MYSTKATcontributes toATMkinase gene expression, further illuminating the mechanism of howATMkinase is up-regulated to respond to DNA damage. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.