Pondering the Promyelocytic Leukemia Protein (PML) Puzzle: Possible Functions for PML Nuclear Bodies

It has become clear that the nucleus is organized into discrete structures. Although not membrane bound, these structures are considered nuclear organelles. Widespread interest in one such nuclear organelle, the promyelocytic leukemia nuclear body (NB), has emerged because of its link to several human disorders, including acute promyelocytic leukemia and AIDS. Studies of the physiological effects of promyelocytic leukemia NBs and the promyelocytic leukemia protein (PML) indicate that these play roles in growth control, transformation suppression, apoptosis and Ras induced senescence. Unfortunately, the molecular and biochemical bases for physiological phenomena associated with PML are not well understood. PML and, by inference, the PML NB have been ascribed apparently disparate roles in transcription, DNA repair, DNA replication, and RNA transport. Its clear physiological importance means that defining a set of discrete biochemical functions for the PML NB is critical. This review focuses on the current theories for molecular and biochemical functions of the PML NB and the supporting evidence for each. PML NBs, also known as PML oncogenic domains, nuclear domain 10's, or Kremer bodies, are currently defined by the presence of PML at these nuclear structures. PML and its associated NBs were first described in a series of studies in the early 1990s which showed that PML was fused to the retinoic acid receptor alpha (RARα) in acute promyelocytic leukemia (APL) patients (reviewed in reference 63). These studies demonstrated that PML NBs were similar to those previously observed by electron microscopy in the 1960s (63). Intriguingly, NBs were disrupted in the APL patients but reformed after treatment with all-trans-retinoic acid (ATRA) (36). Reformation of bodies correlated with remission of disease in patients. This was the first evidence that the integrity of these structures may be critically important to the health of the cell (36, 63). These findings sparked widespread interest in the function of these organelles. These early studies also revealed that the PML protein contained a set of novel zinc-binding domains, known as the RING and B-boxes. Early on, it was proposed that PML utilized these zinc fingers to directly bind DNA and thus alter gene expression. However, in the past 10 years, it has become clear that the RING and B-box domains forge protein associations that are critical to the integrity of this multiprotein complex and subsequent physiological function(s) of this organelle (36, 40, 63). Most reported strategies for assessing PML NB function in essence are designed to answer the following questions: what nuclear structures are the bodies near to, what other macromolecules localize with the body, and what are the effects of disrupting the body? These strategies arise because the discrete biochemical functions of either PML or PML bodies are not known. The results of these strategies and their inherent limitations are discussed within this review. Further, the following considerations should be taken into account in an assessment of PML NB function. First, the expression of the PML gene is not required for viability, since PML−/− mice develop in essence normally and do not get spontaneous cancers at rates higher than do littermate controls (99). Second, the PML gene is not evolutionarily conserved among eukaryotes, being absent in Drosophila melanogaster, Saccharomyces cerevisiae, and Arabidopsis thaliana (see below). Third, unlike other nuclear organelles, there appears to be no PML bodies in Xenopus laevis. However, the disruption of these organelles apparently contributes to human disease. These features and their potential clues to PML NB function are discussed below. Because of space limitations, many topics are not discussed here. For instance, the study of viral systems has been key to our current understanding of the PML NB. However, an in-depth discussion of these contributions is beyond the scope of this review, but this topic is discussed elsewhere (25, 59, 72). Many excellent and comprehensive reviews have been written on various aspects of the physiological functions of PML and its relationship to APL (36, 40, 59, 63, 82). The present review attempts to describe current understanding of the molecular and biochemical underpinnings of PML NB function.