Histone acetyltransferase KAT5

Definition:

Catalytic subunit of the NuA4 histone acetyltransferase complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H2A and H4. Histone acetylation alters nucleosome-DNA interactions and promotes interaction of the modified histones with other proteins which positively regulate transcription. The NuA4 histone acetyltransferase complex is required for the activation of transcriptional programs associated with proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. The NuA4 complex plays a direct role in repair of DNA double-strand breaks (DSBs) by promoting homologous recombination (HR): the complex inhibits TP53BP1 binding to chromatin via MBTD1, which recognizes and binds histone H4 trimethylated at 'Lys-20' (H4K20me), and KAT5 that catalyzes acetylation of 'Lys-15' of histone H2A (H2AK15ac), thereby blocking the ubiquitination mark required for TP53BP1 localization at DNA breaks. Also involved in DSB repair by mediating acetylation of 'Lys-5' of histone H2AX (H2AXK5ac), promoting NBN/NBS1 assembly at the sites of DNA damage. The NuA4 complex plays a key role in hematopoietic stem cell maintenance and is required to maintain acetylated H2A.Z/H2AZ1 at MYC target genes (By similarity). The NuA4 complex is also required for spermatid development by promoting acetylation of histones: histone hyperacetylation is required for histone replacement during the transition from round to elongating spermatids (By similarity). Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome. Also acetylates non-histone proteins, such as BMAL1, ATM, AURKB, CHKA, CGAS, ERCC4/XPF, LPIN1, NDC80/HEC1, NR1D2, RAN, SOX4, FOXP3, ULK1 and RUBCNL/Pacer. Directly acetylates and activates ATM. Promotes nucleotide excision repair (NER) by mediating acetylation of ERCC4/XPF, thereby promoting formation of the ERCC4-ERCC1 complex. Relieves NR1D2-mediated inhibition of APOC3 expression by acetylating NR1D2. Acts as a regulator of regulatory T-cells (Treg) by catalyzing FOXP3 acetylation, thereby promoting FOXP3 transcriptional repressor activity. Involved in skeletal myoblast differentiation by mediating acetylation of SOX4. Catalyzes acetylation of APBB1/FE65, increasing its transcription activator activity. Promotes transcription elongation during the activation phase of the circadian cycle by catalyzing acetylation of BMAL1, promoting elongation of circadian transcripts (By similarity). Together with GSK3 (GSK3A or GSK3B), acts as a regulator of autophagy: phosphorylated at Ser-86 by GSK3 under starvation conditions, leading to activate acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer. Acts as a regulator of the cGAS-STING innate antiviral response by catalyzing acetylation the N-terminus of CGAS, thereby promoting CGAS DNA-binding and activation. Also regulates lipid metabolism by mediating acetylation of CHKA or LPIN1. Promotes lipolysis of lipid droplets following glucose deprivation by mediating acetylation of isoform 1 of CHKA, thereby promoting monomerization of CHKA and its conversion into a tyrosine-protein kinase. Acts as a regulator of fatty-acid-induced triacylglycerol synthesis by catalyzing acetylation of LPIN1, thereby promoting the synthesis of diacylglycerol. In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA) and 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), and is able to mediate protein crotonylation and 2-hydroxyisobutyrylation, respectively. Acts as a key regulator of chromosome segregation and kinetochore-microtubule attachment during mitosis by mediating acetylation or crotonylation of target proteins. Catalyzes acetylation of AURKB at kinetochores, increasing AURKB activity and promoting accurate chromosome segregation in mitosis. Acetylates RAN during mitosis, promoting microtubule assembly at mitotic chromosomes. Acetylates NDC80/HEC1 during mitosis, promoting robust kinetochore-microtubule attachment. Catalyzes crotonylation of MAPRE1/EB1, thereby ensuring accurate spindle positioning in mitosis.

References:

[1]. Arnaud Obri, et al. ANP32E is a histone chaperone that removes H2A.Z from chromatin. Nature. 2014 Jan 30;505(7485):648-53. [Content Brief]

[2]. Scott R Frank, et al. MYC recruits the TIP60 histone acetyltransferase complex to chromatin. EMBO Rep. 2003 Jun;4(6):575-80. [Content Brief]

[3]. Fei Mo, et al. Acetylation of Aurora B by TIP60 ensures accurate chromosomal segregation. Nat Chem Biol. 2016 Apr;12(4):226-32. [Content Brief]

[4]. Gaëlle Legube, et al. Role of the histone acetyl transferase Tip60 in the p53 pathway. J Biol Chem. 2004 Oct 22;279(43):44825-33. [Content Brief]

[5]. Hongmei Cui, et al. The stress-responsive gene ATF3 regulates the histone acetyltransferase Tip60. Nat Commun. 2015 Apr 13;6:6752. [Content Brief]

[6]. He Huang, et al. Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway. Cell Res. 2018 Jan;28(1):111-125. [Content Brief]

[7]. Jiajia Wang, et al. Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex assembly and activation. Nat Commun. 2020 Feb 7;11(1):786. [Content Brief]

[8]. Katrien Berns, et al. A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature. 2004 Mar 25;428(6981):431-7. [Content Brief]

[9]. Rui Liu, et al. Choline kinase alpha 2 acts as a protein kinase to promote lipolysis of lipid droplets. Mol Cell. 2021 Jul 1;81(13):2722-2735.e9. [Content Brief]

[10]. Xiaoling Bao, et al. Mitosis-specific acetylation tunes Ran effector binding for chromosome segregation. J Mol Cell Biol. 2018 Feb 1;10(1):18-32. [Content Brief]

[11]. Ze-Min Song, et al. KAT5 acetylates cGAS to promote innate immune response to DNA virus. Proc Natl Acad Sci U S A. 2020 Sep 1;117(35):21568-21575. [Content Brief]

[12]. Xiaoyu Song, et al. Dynamic crotonylation of EB1 by TIP60 ensures accurate spindle positioning in mitosis. Nat Chem Biol. 2021 Dec;17(12):1314-1323. [Content Brief]

[13]. Tsuyoshi Ikura, et al. DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. Mol Cell Biol. 2007 Oct;27(20):7028-40. [Content Brief]

[14]. S-M Jang, et al. KAT5-mediated SOX4 acetylation orchestrates chromatin remodeling during myoblast differentiation. Cell Death Dis. 2015 Aug 20;6(8):e1857. [Content Brief]

[15]. Yingli Sun, et al. Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. Nat Cell Biol. 2009 Nov;11(11):1376-82. [Content Brief]

[16]. Terytty Yang Li, et al. Tip60-mediated lipin 1 acetylation and ER translocation determine triacylglycerol synthesis rate. Nat Commun. 2018 May 15;9(1):1916. [Content Brief]

[17]. Yingli Sun, et al. A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13182-7. [Content Brief]

[18]. Prisca Brauns-Schubert, et al. CDK9-mediated phosphorylation controls the interaction of TIP60 with the transcriptional machinery. EMBO Rep. 2018 Feb;19(2):244-256. [Content Brief]

[19]. Sabine Probst, et al. Lysine acetyltransferase Tip60 acetylates the APP adaptor Fe65 to increase its transcriptional activity. Biol Chem. 2020 Dec 2;402(4):481-499. [Content Brief]

[20]. Yannick Doyon, et al. Structural and functional conservation of the NuA4 histone acetyltransferase complex from yeast to humans. Mol Cell Biol. 2004 Mar;24(5):1884-96. [Content Brief]

[21]. Raúl García-González, et al. VRK1 Phosphorylates Tip60/KAT5 and Is Required for H4K16 Acetylation in Response to DNA Damage. Cancers (Basel). 2020 Oct 15;12(10):2986. [Content Brief]

[22]. Jiadong Wang, et al. The orphan nuclear receptor Rev-erbbeta recruits Tip60 and HDAC1 to regulate apolipoprotein CIII promoter. Biochim Biophys Acta. 2008 Feb;1783(2):224-36. [Content Brief]

[23]. Xiao Fang, et al. Acetylation of TIP60 at K104 is essential for metabolic stress-induced apoptosis in cells of hepatocellular cancer. Exp Cell Res. 2018 Jan 15;362(2):279-286. [Content Brief]

[24]. Stefan Taubert, et al. E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1. Mol Cell Biol. 2004 May;24(10):4546-56. [Content Brief]

[25]. Gangyin Zhao, et al. Dynamic acetylation of the kinetochore-associated protein HEC1 ensures accurate microtubule-kinetochore attachment. J Biol Chem. 2019 Jan 11;294(2):576-592. [Content Brief]

[26]. Xiawei Cheng, et al. Pacer Is a Mediator of mTORC1 and GSK3-TIP60 Signaling in Regulation of Autophagosome Maturation and Lipid Metabolism. Mol Cell. 2019 Feb 21;73(4):788-802.e7. [Content Brief]

[27]. Bin Li, et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4571-6. [Content Brief]

[28]. Karine Jacquet, et al. The TIP60 Complex Regulates Bivalent Chromatin Recognition by 53BP1 through Direct H4K20me Binding and H2AK15 Acetylation. Mol Cell. 2016 May 5;62(3):409-421. [Content Brief]

[29]. Yannick Doyon, et al. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol Cell. 2006 Jan 6;21(1):51-64. [Content Brief]

[30]. Yan Xiao, et al. Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60. Cell Rep. 2014 Jun 12;7(5):1471-1480. [Content Brief]

[31]. Jonathan Humbert, et al. De Novo KAT5 Variants Cause a Syndrome with Recognizable Facial Dysmorphisms, Cerebellar Atrophy, Sleep Disturbance, and Epilepsy. Am J Hum Genet. 2020 Sep 3;107(3):564-574. [Content Brief]

[32]. Masae Ikura, et al. Acetylation of Histone H2AX at Lys 5 by the TIP60 Histone Acetyltransferase Complex Is Essential for the Dynamic Binding of NBS1 to Damaged Chromatin. Mol Cell Biol. 2015 Dec;35(24):4147-57. [Content Brief]

[33]. Shan-Shan Gao, et al. TIP60 K430 SUMOylation attenuates its interaction with DNA-PKcs in S-phase cells: Facilitating homologous recombination and emerging target for cancer therapy. Sci Adv. 2020 Jul 10;6(28):eaba7822. [Content Brief]

[34]. Misato Kikuchi, et al. TRIM24 mediates ligand-dependent activation of androgen receptor and is repressed by a bromodomain-containing protein, BRD7, in prostate cancer cells. Biochim Biophys Acta. 2009 Dec;1793(12):1828-36. [Content Brief]

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