| Structural highlights
6f0h is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | 6f0f, 6f0g |
| Gene: | ASF1A, CGI-98, HSPC146 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[ASF1A_HUMAN] Histone chaperone that facilitates histone deposition and histone exchange and removal during nucleosome assembly and disassembly. Cooperates with chromatin assembly factor 1 (CAF-1) to promote replication-dependent chromatin assembly and with HIRA to promote replication-independent chromatin assembly. Required for the formation of senescence-associated heterochromatin foci (SAHF) and efficient senescence-associated cell cycle exit.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Anti-silencing function 1 (ASF1) is a conserved H3-H4 histone chaperone involved in histone dynamics during replication, transcription, and DNA repair. Overexpressed in proliferating tissues including many tumors, ASF1 has emerged as a promising therapeutic target. Here, we combine structural, computational, and biochemical approaches to design peptides that inhibit the ASF1-histone interaction. Starting from the structure of the human ASF1-histone complex, we developed a rational design strategy combining epitope tethering and optimization of interface contacts to identify a potent peptide inhibitor with a dissociation constant of 3 nM. When introduced into cultured cells, the inhibitors impair cell proliferation, perturb cell-cycle progression, and reduce cell migration and invasion in a manner commensurate with their affinity for ASF1. Finally, we find that direct injection of the most potent ASF1 peptide inhibitor in mouse allografts reduces tumor growth. Our results open new avenues to use ASF1 inhibitors as promising leads for cancer therapy.
Design on a Rational Basis of High-Affinity Peptides Inhibiting the Histone Chaperone ASF1.,Bakail M, Gaubert A, Andreani J, Moal G, Pinna G, Boyarchuk E, Gaillard MC, Courbeyrette R, Mann C, Thuret JY, Guichard B, Murciano B, Richet N, Poitou A, Frederic C, Le Du MH, Agez M, Roelants C, Gurard-Levin ZA, Almouzni G, Cherradi N, Guerois R, Ochsenbein F Cell Chem Biol. 2019 Nov 21;26(11):1573-1585.e10. doi:, 10.1016/j.chembiol.2019.09.002. Epub 2019 Sep 19. PMID:31543461[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Munakata T, Adachi N, Yokoyama N, Kuzuhara T, Horikoshi M. A human homologue of yeast anti-silencing factor has histone chaperone activity. Genes Cells. 2000 Mar;5(3):221-33. PMID:10759893
- ↑ Mello JA, Sillje HH, Roche DM, Kirschner DB, Nigg EA, Almouzni G. Human Asf1 and CAF-1 interact and synergize in a repair-coupled nucleosome assembly pathway. EMBO Rep. 2002 Apr;3(4):329-34. Epub 2002 Mar 15. PMID:11897662 doi:10.1093/embo-reports/kvf068
- ↑ Umehara T, Horikoshi M. Transcription initiation factor IID-interactive histone chaperone CIA-II implicated in mammalian spermatogenesis. J Biol Chem. 2003 Sep 12;278(37):35660-7. Epub 2003 Jul 2. PMID:12842904 doi:10.1074/jbc.M303549200
- ↑ Tagami H, Ray-Gallet D, Almouzni G, Nakatani Y. Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell. 2004 Jan 9;116(1):51-61. PMID:14718166
- ↑ Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, Erzberger JP, Serebriiskii IG, Canutescu AA, Dunbrack RL, Pehrson JR, Berger JM, Kaufman PD, Adams PD. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell. 2005 Jan;8(1):19-30. PMID:15621527 doi:S1534580704004083
- ↑ Tamburini BA, Carson JJ, Adkins MW, Tyler JK. Functional conservation and specialization among eukaryotic anti-silencing function 1 histone chaperones. Eukaryot Cell. 2005 Sep;4(9):1583-90. PMID:16151251 doi:10.1128/EC.4.9.1583-1590.2005
- ↑ Groth A, Ray-Gallet D, Quivy JP, Lukas J, Bartek J, Almouzni G. Human Asf1 regulates the flow of S phase histones during replicational stress. Mol Cell. 2005 Jan 21;17(2):301-11. PMID:15664198 doi:S1097276504008020
- ↑ Bakail M, Gaubert A, Andreani J, Moal G, Pinna G, Boyarchuk E, Gaillard MC, Courbeyrette R, Mann C, Thuret JY, Guichard B, Murciano B, Richet N, Poitou A, Frederic C, Le Du MH, Agez M, Roelants C, Gurard-Levin ZA, Almouzni G, Cherradi N, Guerois R, Ochsenbein F. Design on a Rational Basis of High-Affinity Peptides Inhibiting the Histone Chaperone ASF1. Cell Chem Biol. 2019 Nov 21;26(11):1573-1585.e10. doi:, 10.1016/j.chembiol.2019.09.002. Epub 2019 Sep 19. PMID:31543461 doi:http://dx.doi.org/10.1016/j.chembiol.2019.09.002
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