MYST-family histone acetyltransferases: beyond chromatin

Abstract

Covalently modifying a protein has proven to be a powerful mechanism of functional regulation. N-epsilon acetylation of lysine residues was initially discovered on histones and has been studied extensively in the context of chromatin and DNA metabolism, such as transcription, replication and repair. However, recent research shows that acetylation is more widespread than initially thought and that it regulates various nuclear as well as cytoplasmic and mitochondrial processes. In this review, we present the multitude of non-histone proteins targeted by lysine acetyltransferases of the large and conserved MYST family, and known functional consequences of this acetylation. Substrates of MYST enzymes include factors involved in transcription, heterochromatin formation and cell cycle, DNA repair proteins, gluconeogenesis enzymes and finally subunits of MYST protein complexes themselves. Discovering novel substrates of MYST proteins is pivotal for the understanding of the diverse functions of these essential acetyltransferases in nuclear processes, signaling, stress response and metabolism.

Fig. 1

The substrates of MYST acetyltransferases can be classified in distinct classes. The majority of the MYST acetyltransferases substrates are nuclear, although cytoplasmic substrates have been reported recently. The best studied MYST substrate class is histones, namely histones H4, H3, H2A and H2A variants. Histone acetylation by MYST proteins has impacts on transcription, DNA repair, DNA replication and other nuclear processes via histone modification crosstalks. Other typical substrates of MYST enzymes are subunits of MYST multiprotein complexes, including MYST proteins themselves. Aceytlation of MYST complex subunits mostly regulates complex stability and possibly target specificity. Another class of MYST substrates are transcription factors whose protein stability and transcription activity can be modified by MYST-dependent acetylation. Proteins involved in DNA damage response can also be acetylated by MYST proteins and this modification can increase kinase activity and checkpoint activation or the choice between cell cycle arrest and apoptosis. Finally, the only known cytoplasmic substrate of MYST enzymes so far is involved in glucose metabolism and acetylation of this substrate by a MYST enzyme regulates their involvement in lifespan elongation. See text for more information

Fig. 2

Effects of acetylation on the non-histone substrates of MYST acetyltransferases. Acetylation of a non-histone substrate by a MYST enzyme can have an impact on its stability and degradation rate. Acetylation can also regulate enzymatic or transcription factor activity. Substrate modification modulates the interaction between proteins, e.g., subunits of the same complex, or affects localization and recruitment to functional sites in the cell