KAT5
Description
The KAT5 (lysine acetyltransferase 5) is a protein-coding gene located on chromosome 11.
KAT5 is a human gene that encodes a histone acetyltransferase enzyme, also known as TIP60. This enzyme belongs to the MYST family of HATs, originally identified as an HIV-1 TAT-interactive protein. KAT5 plays a key role in chromatin remodeling, transcription, DNA repair, and apoptosis. It acetylates both histone and non-histone proteins, influencing various cellular processes. The protein consists of an acetyl CoA binding domain, a zinc finger in the MYST domain, and a CHROMO domain. Excess acetyl CoA is essential for histone acetylation, and the zinc finger domain aids in this process. The CHROMO domain allows KAT5 to bind chromatin, crucial for DNA repair.
KAT5 is the catalytic subunit of the NuA4 histone acetyltransferase complex, a multiprotein complex involved in the transcriptional activation of select genes. This complex primarily acetylates histones H2A and H4, altering nucleosome-DNA interactions and promoting interaction of the modified histones with other proteins that positively regulate transcription. NuA4 is essential for activating transcriptional programs associated with proto-oncogene-mediated growth induction, tumor suppressor-mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 directly participates in DNA double-strand break (DSB) repair by promoting homologous recombination (HR). This involves inhibiting TP53BP1 binding to chromatin via MBTD1, which recognizes and binds histone H4 trimethylated at Lys-20 (H4K20me), and KAT5 catalyzes acetylation of Lys-15 of histone H2A (H2AK15ac), thus blocking the ubiquitination mark required for TP53BP1 localization at DNA breaks. KAT5 also mediates acetylation of Lys-5 of histone H2AX (H2AXK5ac), promoting NBN/NBS1 assembly at the sites of DNA damage. NuA4 is crucial for hematopoietic stem cell maintenance and is required to maintain acetylated H2A.Z/H2AZ1 at MYC target genes. It is also essential for spermatid development by promoting histone acetylation, which is necessary for histone replacement during the transition from round to elongating spermatids. KAT5 is a component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome. In addition to histones, KAT5 also acetylates a variety of non-histone proteins, including BMAL1, ATM, AURKB, CHKA, CGAS, ERCC4/XPF, LPIN1, NDC80/HEC1, NR1D2, RAN, SOX4, FOXP3, SQSTM1, ULK1, and RUBCNL/Pacer. It directly acetylates and activates ATM, promoting nucleotide excision repair (NER) by mediating acetylation of ERCC4/XPF, thereby promoting formation of the ERCC4-ERCC1 complex. KAT5 relieves NR1D2-mediated inhibition of APOC3 expression by acetylating NR1D2. It acts as a regulator of regulatory T-cells (Treg) by catalyzing FOXP3 acetylation, promoting FOXP3 transcriptional repressor activity. KAT5 is involved in skeletal myoblast differentiation by mediating acetylation of SOX4. It catalyzes acetylation of APBB1/FE65, increasing its transcription activator activity. KAT5 promotes transcription elongation during the activation phase of the circadian cycle by catalyzing acetylation of BMAL1, promoting elongation of circadian transcripts. Together with GSK3 (GSK3A or GSK3B), KAT5 acts as a regulator of autophagy. Under starvation conditions, it is phosphorylated at Ser-86 by GSK3, leading to activated acetyltransferase activity and promoting acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer. KAT5 is a regulator of the cGAS-STING innate antiviral response by catalyzing acetylation of the N-terminus of CGAS, promoting CGAS DNA-binding and activation. It also regulates lipid metabolism by mediating acetylation of CHKA or LPIN1. KAT5 promotes lipolysis of lipid droplets following glucose deprivation by mediating acetylation of isoform 1 of CHKA, promoting monomerization of CHKA and its conversion into a tyrosine-protein kinase. It acts as a regulator of fatty-acid-induced triacylglycerol synthesis by catalyzing acetylation of LPIN1, promoting the synthesis of diacylglycerol. Besides protein acetyltransferase, KAT5 can utilize different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA) and 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), mediating protein crotonylation and 2-hydroxyisobutyrylation, respectively. KAT5 is a key regulator of chromosome segregation and kinetochore-microtubule attachment during mitosis by mediating acetylation or crotonylation of target proteins. It catalyzes acetylation of AURKB at kinetochores, increasing AURKB activity and promoting accurate chromosome segregation in mitosis. KAT5 acetylates RAN during mitosis, promoting microtubule assembly at mitotic chromosomes. It acetylates NDC80/HEC1 during mitosis, promoting robust kinetochore-microtubule attachment. KAT5 catalyzes crotonylation of MAPRE1/EB1, ensuring accurate spindle positioning in mitosis.
KAT5 is also known as ESA1, HTATIP, HTATIP1, NEDFASB, PLIP, TIP, TIP60, ZC2HC5, cPLA2.
