Structure, Organization, and Dynamics of Promyelocytic Leukemia Protein Nuclear Bodies

Abstract

The interphase nucleus compartmentalizes its components to give rise to a highly organized and tightly controlled environment. Individual chromosomes occupy discrete areas, termed "chromosome territories," that are separated from each other by a channel called the "interchromosomal domain" (reviewed in Lamond and Earnshaw 1998). Actively transcribed genes tend to be at the periphery of chromosomal territories, whereas newly made RNA transcripts localize into the interchromosomal domain, where they can undergo further processing and transport. Movement within the nucleus (Ferreira et al. 1997) may permit chromosomes to enter "factories" that contain all the necessary enzymatic machinery for replication (reviewed in Jackson 1995).Of the many discrete domains identified throughout the nucleus, the largest are nucleoli, sites of ribosomal RNA synthesis and processing, and sites of preribosomal particle assembly (reviewed in Scheer and Weisenberger 1994). Other subnuclear bodies that appear as punctate structures under immunofluorescence (IF) microscopy include various dynamic structures involved in the maintenance and replication of DNA and RNA synthesis, processing, and transport (reviewed in Nickerson et al. 1995): replication foci, transcript foci, speckled domains, coiled bodies, gems, and promyelocytic leukemia protein (PML) nuclear bodies. Spliceosomal small nuclear (sn) ribonucleoprotein (RNP) components and a subset of non-snRNP splicing factors can be found concentrated in discrete subnuclear domains called "coiled bodies" (Matera and Frey 1998 [in this issue]). It is becoming increasingly apparent that the nucleus has an organization and contains a number of discrete macromolecular domains that coordinate a variety of nuclear processes.

A role for PML and the nuclear body in genomic stability

“…These observations demonstrate that the normal localization pattern of BLM requires intact NBs because its localization can be reconstituted by RA treatment, as has been shown for PML and Sp100 (Dyck et al, 1994;Koken et al, 1994;Weis et al, 1994;Hodges et al, 1998). We conclude therefore that BLM localizes to the NB.…”

“…Anti-BLM staining of unsynchronized cultures of various human cell lines had identi®ed two predominant nuclear localization patterns of BLM (Figure 1c, left panels): (i) discrete, bright dots and (ii) di use microspeckles. As with anti-BLM, staining cells with anti-PML exposed discrete bodies and di use microspeckles ( Figure 1c, central panels, and see Hodges et al, 1998). Superimposition of the stainings with anti-BLM and anti-PML revealed co-localization of BLM and PML to the same discrete, bright dots ( Figure 1c, right panels).…”

“…One distinctive class of subnuclear domains, the PML-nuclear body (NB), appears as punctate speckles by indirect immuno¯uorescence microscopy and is referred to variously as Kremer Bodies, ND10, or PODs (for PML Oncogenic Domains) (for review see Hodges et al, 1998).…”

“…Gene-targeted disruption of PML demonstrates that the PML protein functions as a growth and tumor suppressor in vivo, and it is important for multiple apoptotic pathways (Wang et al, 1998a,b). Interferons, which are potent growth and tumor suppressive cytokines, increase PML expression as well as the size and the number of NBs (Lavau et al, 1995;Stadler et al, 1995;Gaboli et al, 1998;Hodges et al, 1998). However, the mechanisms by which PML exerts its tumor-growth suppressive functions are still to be determined.…”

p53-Mediated Apoptosis and Genomic Instability Diseases

“…One possible mechanism of p53 and BLM interaction in the induction of apoptosis is starting to emerge. BLM localizes in nuclear foci at promyelocytic leukemia (PML) nuclear bodies (NBs) (58,59), structures that also contain PML, hypophosphorylated Rb, SUMO-1, p53, and other proteins (60,61). PML has been implicated in several apoptotic pathways (62,63).…”