Academic journal article Genetics

Chromatin Regulation by the NuA4 Acetyltransferase Complex Is Mediated by Essential Interactions between Enhancer of Polycomb (Epl1) and Esa1

Academic journal article Genetics

Chromatin Regulation by the NuA4 Acetyltransferase Complex Is Mediated by Essential Interactions between Enhancer of Polycomb (Epl1) and Esa1

Article excerpt

EUKARYOTIC genomes are packaged into chromatin, which is composed of nucleosome units containing DNA wrapped around a histone octamer (Kornberg and Lorch 1999). Chromatin is subject to multiple, diverse modes of post-translational regulation that have many established roles, including functions in recombination, DNA damage repair, and transcription (Kouzarides 2007). Acetylation is one such post-translational modification that regulates chromatin function, mediated by the opposing enzymatic activities of lysine acetyltransferases (KATs/HATs) and deacetylases (KDACs/HDACs) (Campos and Reinberg 2009). HATs often exist in large multimeric complexes, such as the deeply conserved NuA4 complex (Doyon et al. 2004).

In humans, the essential catalytic subunit of NuA4, KAT5/ Tip60, along with additional essential subunits such as EPC1/2, are associated with several carcinomas (Avvakumov and Côté 2007; Lafon et al. 2007; Nakahata et al. 2009; Biankin et al. 2012; Huang et al. 2014), suggesting their importance for controlled cellular growth. Much of the basic understanding of NuA4 comes from studies performed in Saccharomyces cerevisiae. NuA4 in yeast includes six essential subunits: Esa1 (Tip60 ortholog), Epl1 (EPC1/2 ortholog), Tra1, Arp4, Act1, and Swc4, all of which are broadly conserved. NuA4 primarily acetylates histones H4 and H2A in vivo (Smith et al. 1998; Clarke et al. 1999) along with noncanonical histones, such as H2A.Z (Keogh et al. 2006), and >250 nonhistone substrates (Lin et al. 2009; Yi et al. 2012; Mitchell et al. 2013; Downey et al. 2015), including 91 essential proteins.

There are two distinct smaller complexes containing NuA4 subunits: piccolo-NuA4, composed of Esa1, Epl1, Yng2, and Eaf6 (Boudreault et al. 2003; Mitchell et al. 2008; Rossetto et al. 2014), and the TINTIN triad of Eaf5/7/3 (Cheng and Côté 2014; Rossetto et al 2014). Piccolo-NuA4 is thought to also exist alone (Ohba et al 1999; Boudreault et al. 2003) and is sufficient for broad nucleosome acetylation in vitro, whereas the NuA4 holo-complex is required for more targeted NuA4 functions such as DNA damage repair and transcriptional activation (Figure 1A) (Bird et al 2002; Boudreault et al. 2003; Selleck et al. 2005; Friis et al. 2009).

Because Esa1 is essential, much of our early understanding of it came from studying hypomorphic alleles, where Esa1 is only partially or conditionally functional (Clarke et al. 1999; Decker et al. 2008). Recently, the first bypass suppressor of Esa1 was identified, where esalD is rescued by loss of the Rpd3L HDAC complex (Torres-Machorro and Pillus 2014). This bypass of Esa1 is promoted by establishing a relatively balanced cellular acetylation state. The discovery of this bypass allowed for the first studies in which cells were completely depleted of Esa1.

Among the six essential NuA4 subunits only Esa1 and Epl1 are found in the very active smaller piccolo complex (Galarneau et al. 2000). Epl1 was first reported as the yeast ortholog of Drosophila melanogaster Enhancer of Polycomb E(Pc), which can function as a suppressor of position-effect variegation and can increase the homeotic phenotype of Polycomb group mutations (Sinclair et al. 1998; Stankunas et al. 1998). Epl1 and E(Pc) are broadly conserved and are orthologous to the EPC1/2 paralogs in humans (Shimono et al. 2000; Doyon et al. 2004).

It is noteworthy that despite its conservation and discovery nearly two decades ago, Epl1 function has been only minimally characterized, primarily based on low-dosage variants, limited in vitro analyses, and most recently when its partial structure bound to nucleosomes was solved (Boudreault et al. 2003; Selleck et al. 2005; Chittuluru et al. 2011; Huang and Tan 2012; Xu et al. 2016). Phenotypes of EPL1 depletion are quite similar to those of impaired ESA1. These include roles in cell-cycle progression through G2/M, H4 acetylation, DNA damage repair, telomeric silencing, and autophagy (Boudreault etal. …

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