MYSTB

TgMYST-B is a nuclear MYST-family lysine acetyltransferase of Toxoplasma gondii that couples histone acetylation to the parasite DNA damage response (PMID:20159970). It shares the MYST domain architecture of its paralog TgMYST-A — a MYST catalytic domain, an atypical C2HC zinc finger, and a chromodomain — and was identified from a ~7.0-kb mRNA (PMID:16339723). TgMYST-B localizes to the nucleus and acetylates histones in vivo; overexpression of the catalytically active enzyme slows parasite growth and protects against a DNA-alkylating agent, while a catalytic-site mutant abolishes both effects, establishing that acetyltransferase activity is required (PMID:20159970). Mechanistically, TgMYST-B localizes to the ATM kinase gene locus and elevates ATM kinase protein and phospho-H2AX levels, and pharmacological inhibition of either ATM kinase or KATs reverses the overexpression-induced slow growth, placing TgMYST-B upstream of ATM kinase in the DNA damage response (PMID:20159970). Beyond this histone-acetylation-to-ATM axis, no further mechanistic detail has been characterized in the available corpus.

1. 2005 Medium

   The question of whether Toxoplasma encodes MYST-family acetyltransferases was answered by identifying two homologues, defining TgMYST-B as a MYST-family lysine acetyltransferase with a conserved catalytic-domain/zinc-finger/chromodomain architecture.

   Evidence Bioinformatic domain analysis and mRNA transcript characterization, with in vitro HAT assay on the paralog TgMYST-A acetylating histone H4

   PMID:16339723

   Open questions at the time

   • TgMYST-B's own enzymatic activity was not directly assayed in this study
   • No in vivo substrate or localization established here
   • Histone-lysine specificity of TgMYST-B not defined
2. 2010 High

   Whether TgMYST-B is a functional nuclear acetyltransferase and whether its catalytic activity drives phenotypes was resolved by showing it is nuclear, acetylates histones in vivo, and that only the catalytically active form slows growth and protects against DNA alkylation.

   Evidence Overexpression of wild-type versus catalytic-mutant tagged TgMYST-B with growth assays, DNA-alkylating challenge, and subcellular localization

   PMID:20159970

   Open questions at the time

   • Endogenous (non-overexpression) function not tested by knockout/knockdown
   • Direct histone-lysine targets in vivo not mapped
   • Mechanism linking acetylation to growth suppression unresolved
3. 2010 Medium

   The pathway connecting TgMYST-B acetyltransferase activity to the DNA damage response was defined by placing it upstream of ATM kinase at the transcriptional level.

   Evidence Immunoblot for ATM and phospho-H2AX, ChIP-localization of TgMYST-B to the ATM kinase gene, and pharmacological epistasis with ATM kinase and KAT inhibitors in overexpression parasites

   PMID:20159970

   Open questions at the time

   • Direct transcriptional activation of the ATM locus versus indirect effect not distinguished
   • Whether histone acetylation at the ATM locus is the causal event not shown
   • Physiological DNA-damage signal that engages TgMYST-B unknown

• The endogenous role of TgMYST-B and its full genomic acetylation targets remain unresolved beyond overexpression phenotypes.
• No loss-of-function (knockout/conditional) analysis in the corpus
• Genome-wide acetylation targets and non-histone substrates unmapped
• Strain-specific behavior not addressed