PML (promyelocytic leukemia)

Alias_symbol (synonym)	MYL
	TRIM19
	RNF71
Other alias
HGNC (Hugo)	PML
LocusID (NCBI)	5371
Atlas_Id	41
Location	15q24.1  [Link to chromosome band 15q24]
Location_base_pair	Starts at 73994673 and ends at 74036394 bp from pter ( according to hg19-Feb_2009)  [Mapping PML.png]
	Top: Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Bottom: Metaphase FISH analysis of PML (green); red dots indicate centromere of chromosome 15 (Subramaniyam et al., 2006).

	Structural organization of PML human gene (Nisole et al., 2013).
Description	PML is composed of 9 exons. Exons 7 and 8 can be divided into exons 7a, 7b, 8a and 8b.
Transcription	Transcription of PML generates 22 transcripts (splice variants) with at least 11 different isoforms (PMLI, PMLIa, PMLII, PMLIIa, PMLIII, PMLIV, PMLIVa, PMLV, PMLVI, PMLVIIa, PMLVIIb). Names of PML isoforms are based on the original nomenclature defined by Jensen et al., 2001.
Pseudogene	No pseudogenes have been reported so far.

	Schematic representation of PML isoforms (Nisole et al., 2013).
Description	Alternative splicing of PML gives rise to several isoforms with different molecular weight: PMLI is the longest isoform and is composed of 882 amino acids, while the shortest is PMLVIIb (435 amino acids). PML belongs to the family of the tripartite motif (TRIM). The RBCC/TRIM motif is present in all PML isoforms and is encoded by the exons 1-3. The RBCC domain is composed of a RING finger domain (R), two B-boxes domains (B1 and B2) and an α-helical coiled-coil domain (CC). The RING finger motif is a conserved cysteine-rich zinc-binding domain found in several classes of proteins. The RING domain of PML is involved in the formation of the PML nuclear bodies (PML-NBs, see below) and in several others PML functions. Adjacent to the RING domain lay two cysteine-rich domains named B-boxes: these two domains have been proposed to work as second zinc-binding domain and they are involved in PML-NBs formation and in several others PML functions. The coiled-coil domain mediate PML homo- and hetero-dimerization. The CC domain is also essential for PML-NBs formation and PML functions. A nuclear localization signal (NLS) is present in the isoforms but not in PMLVIIb. The SUMO interacting motif (SIM) of PML is required for the recognition and binding of SUMOylated proteins (Jensen et al., 2001; Nisole et al., 2013). The SIM domain also contains the PML degron, involved in the CK2-dependent PML degradation (Scaglioni et al., 2006). PML undergoes several post-translational modifications. Several kinases phosphorylate PML on serine and threonine residues regulating its functions (Bernardi et al., 2004; Hayakawa and Privalsky, 2004; Scaglioni et al., 2006; Yang et al., 2006). SUMOylation is the most intensely studied post-translational modification of PML. Both SUMO1 and SUMO2/SUMO3 bind covalently to PML. SUMOylation facilitates PML-NBs formation promoting tumor suppressive response PML-dependent, but also promotes leukemogenesis by the SUMOylation of PML-RARA. Finally, SUMOylation also promotes ubiquitin-mediate degradation of PML and PML-RARA (Fu et al., 2005; Shen et al., 2006; Lallemand-Breitenbach et al., 2008; Kamitani et al., 1998a; Kamitani et al., 1998b; Rabellino et al., 2012). Ubiquitination regulates PML functions and activity and deregulation of PML appears to be the common mechanism accounting for PML loss in tumors (reviewed in Rabellino and Scaglioni, 2013). Finally, PML can be also acetylated (Hayakawa et al., 2008). PML is the major constituent of the PML-NBs. PML-NBs are highly dynamic nuclear structures tightly bound to the nuclear matrix. Several functions of PML are related to the PML-NBs functions (reviewed in Bernardi et al., 2007). More than 150 different proteins have been shown to localize into PML-NBs (Van Damme et al., 2010).
	Schematic representation of PML isoform IV protein domains. R = RING-finger domains, aa 55-91; B1, B2 = B-boxes 1 aa 124-166 and 2 aa 184-228; CC = α-helical coiled-coil domain, aa 233-360; N = nuclear localization signal, aa 428-442; SIM = SUMO interacting motif, 508-518; D = degron. The three major SUMOylation sites (K60, K160 and K442) are indicated, as well as the major phosphorylation sites (T28, S36, S40, S480, T482, S517).
Expression	PML is ubiquitously expressed.
Localisation	Nuclear (PMLI-VI) and cytoplasmic (PMLVIIb).
Function	PML has been implicated in several cellular functions. Cellular senescence: PML is a key regulator of cellular senescence. PML is involved in oncogenic-induced senescence (OIS) K-RAS dependent in a p53 dependent way (de Stanchina et al., 2004; Ferbeyre et al., 2000; Pearson et al., 2000; Scaglioni et al., 2012). PML is also involved in Rb-dependent senescence (Mallette et al., 2004). Apoptosis: PML promotes apoptosis primarily by its ability to interact with p53 (Wang et al., 1998). Moreover, a pro-apoptotic function has been also attributed to the cytoplasmic isoform of PML (Giorgi et al., 2010). Neoangiogenesis: PML represses HIF1 transcription, blocking de novo angiogenesis (Bernardi et al., 2006). Cell migration: PML is involved in the regulation of cell migration by the negatively regulating of β-1 integrins (Reineke et al., 2010). DNA damage response: several proteins involved in DNA repair have been report to reside into PML-NBs. Therefore, PML is also involved in DNA-repair, even though the mechanisms are still not completely clear (reviewed in Dellaire and Bazett-Jones, 2004). Anti-viral response: several viral proteins interact with PML and the PML-NBs; moreover, several reports implicate PML and PML-NBs in anti-viral response (reviewed in Geoffroy and Chelbi-Alix, 2011). Hematopoietic stem cell maintenance: PML has been reported being involved in hematopoietic stem cell maintenance by the regulation of the fatty acid oxidation (Ito et al., 2008; Ito et al., 2012). Several functions of PML are related to its ability to form PML-NBs. PML-NBs have been involved in tumor suppression, senescence and apoptosis, DNA-damage response, cell migration, neoangiogenesis and anti-viral response (reviewed in Bernardi et al., 2007).
Homology	PML is conserved in Amniota (source: HomoloGene).

Note	PML-RARA is the product of the chromosomal translocation t(15;17) and it causes acute promyelocytic leukemia (APL) (de Thé et al., 1990; Goddard et al., 1991; Kakizuka et al., 1991; Pandolfi et al., 1991).
	Schematic representation of the mutations type of human PML found in human tumor samples (source COSMIC).
Germinal	No germinal mutations of PML have been reported.
Somatic	At least 65 different somatic mutations have been described. All the informations in this regard can be found at the COSMIC website.

Note	Breakpoint at q24, responsible of translocation t(15;17)(q24;q21).

Search in all EBI   NCBI

For comments and suggestions or contributions, please contact us