Complex Functions of Gcn5 and Pcaf in Development and Disease

Overview

Journal Biochim Biophys Acta Gene Regul Mech

Publisher Elsevier

Specialties Biochemistry
Biophysics
Genetics
Molecular Biology

Date 2020 Jul 31

PMID 32730897

Citations 18

Authors

Evangelia Koutelou

Aimee T Farria

Sharon Y R Dent

Affiliations

Soon will be listed here.

Abstract

A wealth of biochemical and cellular data, accumulated over several years by multiple groups, has provided a great degree of insight into the molecular mechanisms of actions of GCN5 and PCAF in gene activation. Studies of these lysine acetyltransferases (KATs) in vitro, in cultured cells, have revealed general mechanisms for their recruitment by sequence-specific binding factors and their molecular functions as transcriptional co-activators. Genetic studies indicate that GCN5 and PCAF are involved in multiple developmental processes in vertebrates, yet our understanding of their molecular functions in these contexts remains somewhat rudimentary. Understanding the functions of GCN5/PCAF in developmental processes provides clues to the roles of these KATs in disease states. Here we will review what is currently known about the developmental roles of GCN5 and PCAF, as well as emerging role of these KATs in oncogenesis.

Citing Articles

KAT2B inhibits proliferation and invasion via inactivating TGF-β/Smad3 pathway-medicated autophagy and EMT in epithelial ovarian cancer.

Yao Y, Niu Y, Zhou H, Yong M Sci Rep. 2025; 15(1):3417.

PMID: 39870682 PMC: 11772695. DOI: 10.1038/s41598-024-83977-1.

The combination of decitabine with multi-omics confirms the regulatory pattern of the correlation between DNA methylation of the CACNA1C gene and atrial fibrillation.

Yang Y, Li Q, Liu X, Shao C, Yang H, Niu S Front Pharmacol. 2024; 15:1497977.

PMID: 39734414 PMC: 11681619. DOI: 10.3389/fphar.2024.1497977.

Transcriptomic and Metabolomic Analysis Reveals Multifaceted Impact of Gcn5 Knockdown in Development.

Li Y, Xu Y, Li R, Huang S, Wu Q, Yan J Metabolites. 2024; 14(12).

PMID: 39728461 PMC: 11678289. DOI: 10.3390/metabo14120680.

Targeting lysine acetylation readers and writers.

Zhou M, Cole P Nat Rev Drug Discov. 2024; 24(2):112-133.

PMID: 39572658 PMC: 11798720. DOI: 10.1038/s41573-024-01080-6.

The MYC-MAF-SAGA axis drives oncogenic gene expression in multiple myeloma.

Wang H, Wen H, Shi X Genes Dev. 2024; 38(15-16):693-694.

PMID: 39168637 PMC: 11444177. DOI: 10.1101/gad.352186.124.

References

Ianari A, Gallo R, Palma M, Alesse E, Gulino A . Specific role for p300/CREB-binding protein-associated factor activity in E2F1 stabilization in response to DNA damage. J Biol Chem. 2004; 279(29):30830-5. DOI: 10.1074/jbc.M402403200. View

Wang L, Koutelou E, Hirsch C, McCarthy R, Schibler A, Lin K . GCN5 Regulates FGF Signaling and Activates Selective MYC Target Genes during Early Embryoid Body Differentiation. Stem Cell Reports. 2017; 10(1):287-299. PMC: 5768892. DOI: 10.1016/j.stemcr.2017.11.009. View

Dou Y, Milne T, Tackett A, Smith E, Fukuda A, Wysocka J . Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell. 2005; 121(6):873-85. DOI: 10.1016/j.cell.2005.04.031. View

Soffers J, Li X, Saraf A, Seidel C, Florens L, Washburn M . Characterization of a metazoan ADA acetyltransferase complex. Nucleic Acids Res. 2019; 47(7):3383-3394. PMC: 6468242. DOI: 10.1093/nar/gkz042. View

Warrier S, Nuwayhid S, Sabatino J, Sugrue K, Zohn I . Supt20 is required for development of the axial skeleton. Dev Biol. 2016; 421(2):245-257. PMC: 5209264. DOI: 10.1016/j.ydbio.2016.11.009. View

Zohn I, Li Y, Skolnik E, Anderson K, Han J, Niswander L . p38 and a p38-interacting protein are critical for downregulation of E-cadherin during mouse gastrulation. Cell. 2006; 125(5):957-69. DOI: 10.1016/j.cell.2006.03.048. View

Korzus E, Torchia J, Rose D, Xu L, Kurokawa R, McInerney E . Transcription factor-specific requirements for coactivators and their acetyltransferase functions. Science. 1998; 279(5351):703-7. DOI: 10.1126/science.279.5351.703. View

Blanco-Garcia N, Asensio-Juan E, de la Cruz X, Martinez-Balbas M . Autoacetylation regulates P/CAF nuclear localization. J Biol Chem. 2008; 284(3):1343-52. DOI: 10.1074/jbc.M806075200. View

Chen Y, Gatchel J, Lewis R, Mao C, Grant P, Zoghbi H . Gcn5 loss-of-function accelerates cerebellar and retinal degeneration in a SCA7 mouse model. Hum Mol Genet. 2011; 21(2):394-405. PMC: 3276287. DOI: 10.1093/hmg/ddr474. View

10.

Mohibi S, Srivastava S, Bele A, Mirza S, Band H, Band V . Acetylation of Mammalian ADA3 Is Required for Its Functional Roles in Histone Acetylation and Cell Proliferation. Mol Cell Biol. 2016; 36(19):2487-502. PMC: 5021379. DOI: 10.1128/MCB.00342-16. View

11.

Urvalek A, Wang X, Lu H, Zhao J . KLF8 recruits the p300 and PCAF co-activators to its amino terminal activation domain to activate transcription. Cell Cycle. 2010; 9(3):601-11. PMC: 2888133. DOI: 10.4161/cc.9.3.10606. View

12.

Linares L, Kiernan R, Triboulet R, Chable-Bessia C, Latreille D, Cuvier O . Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2. Nat Cell Biol. 2007; 9(3):331-8. DOI: 10.1038/ncb1545. View

13.

Ogryzko V, Kotani T, Zhang X, Schiltz R, Howard T, Yang X . Histone-like TAFs within the PCAF histone acetylase complex. Cell. 1998; 94(1):35-44. DOI: 10.1016/s0092-8674(00)81219-2. View

14.

Yamauchi T, Yamauchi J, Kuwata T, Tamura T, Yamashita T, Bae N . Distinct but overlapping roles of histone acetylase PCAF and of the closely related PCAF-B/GCN5 in mouse embryogenesis. Proc Natl Acad Sci U S A. 2000; 97(21):11303-6. PMC: 17195. DOI: 10.1073/pnas.97.21.11303. View

15.

Hitachi K, Nakatani M, Takasaki A, Ouchi Y, Uezumi A, Ageta H . promoter-associated lncRNA is essential for myogenic differentiation. EMBO Rep. 2019; 20(3). PMC: 6399612. DOI: 10.15252/embr.201847468. View

16.

Svensson K, Tahvilian S, Martins V, Dent J, Lemanek A, Barooni N . Combined overexpression of SIRT1 and knockout of GCN5 in adult skeletal muscle does not affect glucose homeostasis or exercise performance in mice. Am J Physiol Endocrinol Metab. 2019; 318(2):E145-E151. PMC: 7052578. DOI: 10.1152/ajpendo.00370.2019. View

17.

Stilling R, Ronicke R, Benito E, Urbanke H, Capece V, Burkhardt S . K-Lysine acetyltransferase 2a regulates a hippocampal gene expression network linked to memory formation. EMBO J. 2014; 33(17):1912-27. PMC: 4195786. DOI: 10.15252/embj.201487870. View

18.

Mao X, Gluck N, Li D, Maine G, Li H, Zaidi I . GCN5 is a required cofactor for a ubiquitin ligase that targets NF-kappaB/RelA. Genes Dev. 2009; 23(7):849-61. PMC: 2666342. DOI: 10.1101/gad.1748409. View

19.

Manickavinayaham S, Velez-Cruz R, Biswas A, Bedford E, Klein B, Kutateladze T . E2F1 acetylation directs p300/CBP-mediated histone acetylation at DNA double-strand breaks to facilitate repair. Nat Commun. 2019; 10(1):4951. PMC: 6821830. DOI: 10.1038/s41467-019-12861-8. View

20.

Sawan C, Hernandez-Vargas H, Murr R, Lopez F, Vaissiere T, Ghantous A . Histone acetyltransferase cofactor Trrap maintains self-renewal and restricts differentiation of embryonic stem cells. Stem Cells. 2013; 31(5):979-91. DOI: 10.1002/stem.1341. View