Abstract
Chromatin-modifying enzymes and ATP-dependent remodeling complexes have been intensely studied individually, yet how these activities are coordinated to ensure essential cell functions such as transcription, replication, and repair of damage is not well understood. In this study, we show that the critical loss of Sas3 and Gcn5 acetyltransferases in yeast can be functionally rescued by inactivation of ISWI remodelers. This genetic interaction depends on the ATPase activities of Isw1 and Isw2, suggesting that it involves chromatin remodeling activities driven by the enzymes. Genetic dissection of the Isw1 complexes reveals that the antagonistic effects are mediated specifically by the Isw1a complex. Loss of Sas3 and Gcn5 correlates with defective RNA polymerase II (RNAPII) occupancy at actively transcribed genes, as well as a significant loss of H3K14 acetylation. Inactivation of the Isw1a complex in the acetyltransferase mutants restores RNAPII recruitment at active genes, indicating that transcriptional regulation may be the mechanism underlying suppression. Dosage studies and further genetic dissection reveal that the Isw1b complex may act in suppression through down-regulation of Isw1a. These studies highlight the importance of balanced chromatin modifying and remodeling activities for optimal transcription and cell growth.
Highlights
Two major classes of enzymes regulate the architecture of chromatin and are thereby critical for DNA-templated processes such as transcription, replication, and repair of damage
We show that the critical loss of Sas3 and Gcn5 acetyltransferases can be functionally rescued by inactivation of ISWI remodelers
Because inactivation of the ATPase function of Isw1 consistently resulted in a stronger rescue phenotype than that of Isw2, we focused on dissecting the mechanism underlying the potential antagonism between ISW1 remodeling and acetyltransferase activities mediated by SAS3 and GCN5
Summary
Two major classes of enzymes regulate the architecture of chromatin and are thereby critical for DNA-templated processes such as transcription, replication, and repair of damage. Remodeling enzymes use the energy of ATP hydrolysis to alter the structure or position of nucleosomes (reviewed in [1,2]), whereas chromatin modifying enzymes act post-translationally on multiple nuclear substrates. Prominent among these are the nucleosomal histones that are extensively modified on their N- and C-terminal tails (reviewed in [3]). Histone acetylation can be recognized by bromodomains, whereas histone methylation is recognized by chromo-like-domains and PHD domains (reviewed in [4]) These domains are found in many nuclear proteins, including chromatin modifying enzymes and remodeling complexes
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