| Structural highlights
Disease
PML_HUMAN Note=A chromosomal aberration involving PML may be a cause of acute promyelocytic leukemia (APL). Translocation t(15;17)(q21;q21) with RARA. The PML breakpoints (type A and type B) lie on either side of an alternatively spliced exon.[1] [2]
Function
MALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.PML_HUMAN Key component of PML nuclear bodies that regulate a large number of cellular processes by facilitating post-translational modification of target proteins, promoting protein-protein contacts, or by sequestering proteins. Functions as tumor suppressor. Required for normal, caspase-dependent apoptosis in response to DNA damage, FAS, TNF, or interferons. Plays a role in transcription regulation, DNA damage response, DNA repair and chromatin organization. Plays a role in processes regulated by retinoic acid, regulation of cell division, terminal differentiation of myeloid precursor cells and differentiation of neural progenitor cells. Required for normal immunity to microbial infections. Plays a role in antiviral response. In the cytoplasm, plays a role in TGFB1-dependent processes. Regulates p53/TP53 levels by inhibiting its ubiquitination and proteasomal degradation. Regulates activation of p53/TP53 via phosphorylation at 'Ser-20'. Sequesters MDM2 in the nucleolus after DNA damage, and thereby inhibits ubiquitination and degradation of p53/TP53. Regulates translation of HIF1A by sequestering MTOR, and thereby plays a role in neoangiogenesis and tumor vascularization. Regulates RB1 phosphorylation and activity. Required for normal development of the brain cortex during embryogenesis. Can sequester herpes virus and varicella virus proteins inside PML bodies, and thereby inhibit the formation of infectious viral particles. Regulates phosphorylation of ITPR3 and plays a role in the regulation of calcium homeostasis at the endoplasmic reticulum (By similarity). Regulates transcription activity of ELF4. Inhibits specifically the activity of the tetrameric form of PKM. Together with SATB1, involved in local chromatin-loop remodeling and gene expression regulation at the MHC-I locus. Regulates PTEN compartmentalization through the inhibition of USP7-mediated deubiquitination.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]
Publication Abstract from PubMed
PML Nuclear Bodies (NBs) are disrupted in PML-RARA-driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% APL patients, driving PML-RARA degradation and NB reformation. In non-APL cells, arsenic binding onto PML also amplifies NB formation. Yet, the actual molecular mechanism(s) involved remain(s) elusive. Here, we establish that PML NBs display some features of liquid-liquid phase separation and that ATO induces a gel-like transition. PML B-box-2 structure reveals an alpha helix driving B2 trimerization and positioning a cysteine trio to form an ideal arsenic-binding pocket. Altering either of the latter impedes ATO-driven NB-assembly, PML sumoylation and PML-RARA degradation, mechanistically explaining clinical ATO-resistance. This B2 trimer and the C213 trio create an oxidation-sensitive rheostat that controls PML NB assembly dynamics and downstream signaling in both basal state and during stress response. These findings identify the structural basis for arsenic targeting of PML which could pave the way to novel cancer drugs.
Structural basis of PML/RARA oncoprotein targeting by arsenic unravels a cysteine rheostat controlling PML body assembly and function.,Bercier P, Wang QQ, Zang N, Zhang J, Yang C, Maimaitiyiming Y, Abou-Ghali M, Berthier C, Wu C, Niwa-Kawakita M, Dirami T, Geoffroy MC, Ferhi O, Quentin S, Benhenda S, Ogra Y, Gueroui Z, Zhou C, Naranmandura H, de The H, Lallemand-Breitenbach V Cancer Discov. 2023 Sep 1. doi: 10.1158/2159-8290.CD-23-0453. PMID:37655965[21]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ de The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell. 1991 Aug 23;66(4):675-84. PMID:1652369
- ↑ Goddard AD, Borrow J, Freemont PS, Solomon E. Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science. 1991 Nov 29;254(5036):1371-4. PMID:1720570
- ↑ Kamitani T, Kito K, Nguyen HP, Wada H, Fukuda-Kamitani T, Yeh ET. Identification of three major sentrinization sites in PML. J Biol Chem. 1998 Oct 9;273(41):26675-82. PMID:9756909
- ↑ Zhong S, Delva L, Rachez C, Cenciarelli C, Gandini D, Zhang H, Kalantry S, Freedman LP, Pandolfi PP. A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARalpha and T18 oncoproteins. Nat Genet. 1999 Nov;23(3):287-95. PMID:10610177 doi:10.1038/15463
- ↑ Zhong S, Salomoni P, Ronchetti S, Guo A, Ruggero D, Pandolfi PP. Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis. J Exp Med. 2000 Feb 21;191(4):631-40. PMID:10684855
- ↑ Guo A, Salomoni P, Luo J, Shih A, Zhong S, Gu W, Pandolfi PP. The function of PML in p53-dependent apoptosis. Nat Cell Biol. 2000 Oct;2(10):730-6. PMID:11025664 doi:10.1038/35036365
- ↑ Regad T, Saib A, Lallemand-Breitenbach V, Pandolfi PP, de The H, Chelbi-Alix MK. PML mediates the interferon-induced antiviral state against a complex retrovirus via its association with the viral transactivator. EMBO J. 2001 Jul 2;20(13):3495-505. PMID:11432836 doi:10.1093/emboj/20.13.3495
- ↑ Yang S, Kuo C, Bisi JE, Kim MK. PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nat Cell Biol. 2002 Nov;4(11):865-70. PMID:12402044 doi:10.1038/ncb869
- ↑ Blondel D, Regad T, Poisson N, Pavie B, Harper F, Pandolfi PP, De The H, Chelbi-Alix MK. Rabies virus P and small P products interact directly with PML and reorganize PML nuclear bodies. Oncogene. 2002 Nov 14;21(52):7957-70. PMID:12439746 doi:10.1038/sj.onc.1205931
- ↑ Louria-Hayon I, Grossman T, Sionov RV, Alsheich O, Pandolfi PP, Haupt Y. The promyelocytic leukemia protein protects p53 from Mdm2-mediated inhibition and degradation. J Biol Chem. 2003 Aug 29;278(35):33134-41. Epub 2003 Jun 16. PMID:12810724 doi:10.1074/jbc.M301264200
- ↑ Suico MA, Yoshida H, Seki Y, Uchikawa T, Lu Z, Shuto T, Matsuzaki K, Nakao M, Li JD, Kai H. Myeloid Elf-1-like factor, an ETS transcription factor, up-regulates lysozyme transcription in epithelial cells through interaction with promyelocytic leukemia protein. J Biol Chem. 2004 Apr 30;279(18):19091-8. Epub 2004 Feb 19. PMID:14976184 doi:10.1074/jbc.M312439200
- ↑ Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol. 2004 Jul;6(7):665-72. Epub 2004 Jun 13. PMID:15195100 doi:10.1038/ncb1147
- ↑ Lin HK, Bergmann S, Pandolfi PP. Cytoplasmic PML function in TGF-beta signalling. Nature. 2004 Sep 9;431(7005):205-11. PMID:15356634 doi:10.1038/nature02783
- ↑ Dellaire G, Ching RW, Ahmed K, Jalali F, Tse KC, Bristow RG, Bazett-Jones DP. Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR. J Cell Biol. 2006 Oct 9;175(1):55-66. PMID:17030982 doi:10.1083/jcb.200604009
- ↑ Shimada N, Shinagawa T, Ishii S. Modulation of M2-type pyruvate kinase activity by the cytoplasmic PML tumor suppressor protein. Genes Cells. 2008 Mar;13(3):245-54. doi: 10.1111/j.1365-2443.2008.01165.x. PMID:18298799 doi:10.1111/j.1365-2443.2008.01165.x
- ↑ Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J, Pandolfi PP. The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature. 2008 Oct 9;455(7214):813-7. doi: 10.1038/nature07290. Epub 2008 Aug 20. PMID:18716620 doi:10.1038/nature07290
- ↑ Kumar PP, Bischof O, Purbey PK, Notani D, Urlaub H, Dejean A, Galande S. Functional interaction between PML and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus. Nat Cell Biol. 2007 Jan;9(1):45-56. Epub 2006 Dec 17. PMID:17173041 doi:10.1038/ncb1516
- ↑ Oh W, Ghim J, Lee EW, Yang MR, Kim ET, Ahn JH, Song J. PML-IV functions as a negative regulator of telomerase by interacting with TERT. J Cell Sci. 2009 Aug 1;122(Pt 15):2613-22. doi: 10.1242/jcs.048066. Epub 2009 Jun, 30. PMID:19567472 doi:10.1242/jcs.048066
- ↑ Cuchet D, Sykes A, Nicolas A, Orr A, Murray J, Sirma H, Heeren J, Bartelt A, Everett RD. PML isoforms I and II participate in PML-dependent restriction of HSV-1 replication. J Cell Sci. 2011 Jan 15;124(Pt 2):280-91. doi: 10.1242/jcs.075390. Epub 2010 Dec , 20. PMID:21172801 doi:10.1242/jcs.075390
- ↑ Reichelt M, Wang L, Sommer M, Perrino J, Nour AM, Sen N, Baiker A, Zerboni L, Arvin AM. Entrapment of viral capsids in nuclear PML cages is an intrinsic antiviral host defense against varicella-zoster virus. PLoS Pathog. 2011 Feb 3;7(2):e1001266. doi: 10.1371/journal.ppat.1001266. PMID:21304940 doi:10.1371/journal.ppat.1001266
- ↑ Bercier P, Wang QQ, Zang N, Zhang J, Yang C, Maimaitiyiming Y, Abou-Ghali M, Berthier C, Wu C, Niwa-Kawakita M, Dirami T, Geoffroy MC, Ferhi O, Quentin S, Benhenda S, Ogra Y, Gueroui Z, Zhou C, Naranmandura H, de The H, Lallemand-Breitenbach V. Structural basis of PML/RARA oncoprotein targeting by arsenic unravels a cysteine rheostat controlling PML body assembly and function. Cancer Discov. 2023 Sep 1. PMID:37655965 doi:10.1158/2159-8290.CD-23-0453
|
