Understanding HAT1: A Comprehensive Review of Noncanonical Roles and Connection with Disease

Abstract

Histone acetylation plays a vital role in organizing chromatin, regulating gene expression and controlling the cell cycle. The first histone acetyltransferase to be identified was histone acetyltransferase 1 (HAT1), but it remains one of the least understood acetyltransferases. HAT1 catalyzes the acetylation of newly synthesized H4 and, to a lesser extent, H2A in the cytoplasm. However, 20 min after assembly, histones lose acetylation marks. Moreover, new noncanonical functions have been described for HAT1, revealing its complexity and complicating the understanding of its functions. Recently discovered roles include facilitating the translocation of the H3H4 dimer into the nucleus, increasing the stability of the DNA replication fork, replication-coupled chromatin assembly, coordination of histone production, DNA damage repair, telomeric silencing, epigenetic regulation of nuclear lamina-associated heterochromatin, regulation of the NF-κB response, succinyl transferase activity and mitochondrial protein acetylation. In addition, the functions and expression levels of HAT1 have been linked to many diseases, such as many types of cancer, viral infections (hepatitis B virus, human immunodeficiency virus and viperin synthesis) and inflammatory diseases (chronic obstructive pulmonary disease, atherosclerosis and ischemic stroke). The collective data reveal that HAT1 is a promising therapeutic target, and novel therapeutic approaches, such as RNA interference and the use of aptamers, bisubstrate inhibitors and small-molecule inhibitors, are being evaluated at the preclinical level.

Keywords: HAT1; acetyltransferase; cancer; epigenetics; histones H3H4; immunoinflammatory diseases; noncanonical roles; translational opportunities; viral infections.

Figure 1

Scheme of complexes of HAT1 in nucleus (NuB4 complex) and cytoplasm compared in mammals and yeast. HAT1: histone acetyltransferase 1, NASP: nuclear autoantigenic sperm protein, RbAp46: Retinoblastoma protein-associated protein 46.

Figure 2

Overview of canonical and noncanonical functions of HAT1. Center: canonical role of HAT1 consists of the acetylation of newly synthesized H4 histones in the cytoplasm. Peripheral: non-canonical roles of HAT1 encompass: (1) Translocation of H3H4 into nucleus, (2) DNA replication fork stability and replication-coupled chromatin assembly, (3) Coordination of histone production, (4) DNA damage repair, (5) Telomeric silencing, (6) Epigenetic regulation of nuclear lamina-associated heterochomatin, (7) Acetylation of PLZF, (8) Succinyl transferase activity and (9) Mitochondrial protein acetylation. HAT1 = histone acetyltransferase 1, RbAp46 = pRB-associated protein p46, Asf-1 = anti-silencing factor 1, DSB = double-strand break, PLZF = promyelocytic leukemia zinc finger, PGAM = phosphoglycerate mutase, MEF = mouse embryonic fibroblast.