The<unk> -NBs have a wide array of functions, and a large role in cell regulation. They exert their wide range of actions through interactions with varying proteins localized to the<unk> -NBs. It is thought that the specific biochemical function performed by<unk> -NBs may be serving as an E3 ligase for the sumoylation of other proteins. The true function, however, remains unclear, and several possible models have been proposed for<unk> -NB function, including nuclear storage of proteins, serving as a dock where other proteins accumulate to be post-translationally modified, direct involvement with transcription, and chromatin regulation.<unk> -NBs also play a role in transcriptional regulation.<unk> -NBs have been shown to increase the transcription of some genes, while repressing the transcription of other genes. It has been suggested that the mechanism by which<unk> -NBs do this is via a chromatin-remodelling processes, although this is uncertain. Due to this apparent contradiction, it is possible that<unk> -NBs may be heterogeneous structures that have different functions based on their location within the nucleus, the proteins they interact with in a specific area of the nucleus, or the specific<unk>  protein isoforms of which they are composed. In addition to this regulation of transcription, observations of<unk> -NBs have strongly suggested that the protein complex plays a role in mediating DNA-damage responses. For example, the number and size of<unk> -NBs increases as the activities of DNA damage sensors ATM and ATR increase. The nuclear bodies localize to the site of DNA damage, where proteins associated with the repair of DNA and halting of the cell cycle then co-localize. The functional purpose of the interaction between<unk> -NBs and DNA repair mechanisms remains unclear, but it seems unlikely that they have a role in repairing the DNA directly, due to the co-localization of DNA repair proteins and<unk> -NBs some time after the DNA has been damaged. Rather, it is thought that<unk> -NBs may regulate responses to DNA damage by acting as a storage site for proteins involved in DNA repair, regulating the repair directly, or mediating between DNA repair and checkpoint responses. However, it is clear that<unk> -NBs play a role in mediating checkpoint responses, particularly in causing apoptosis.<unk>  plays an important role in both p53 dependent and p53 independent apoptotic pathways.<unk>  activates p53 by recruiting the protein to a<unk> -NBs site and promoting its activation, while inhibiting regulators of the protein such as MDM2 or HAUSP. In pathways that do not use p53 in inducing apoptosis,<unk>  have been shown to interact with CHK2 and induce it to autophosphorylate to become active. In addition to those two apoptotic pathways, Fas-induced apoptosis relies on the<unk> -NBs to release FLICE-Associated huge protein, which then localizes to the mitochondria to promote the activation of Caspase-8. Beyond apoptosis, other studies have implicated<unk> -NBs in cellular senescence, particularly its induction. It has been shown to be involved with the formation of certain chromatin features of cells experiencing senescence, such as senescence-associated heterochromatin foci (SAHFs), which are believed to suppress the expression of growth-promoting factors and genes. The formation of these features is the result of histone chaperones, HIRA and ASF1, whose chromatin remodeling activities here are mediated by the<unk> -NBs. HIRA localizes to<unk> -NBs before any other interaction occurs with the DNA. Role in Cancer Loss of function mutations of the<unk>  protein, particularly resulting from the fusion of the<unk>  gene with RARα gene in Acute<unk>  leukemias, is implicated in several tumor suppressing apoptotic pathways, particularly those that rely on p53 as noted above. Thus, the loss of<unk>  function confers a cellular survival and proliferation advantage, impedes cellular senescence through loss of SAHFs, and puts a block on cellular differentiation. Both humans and mice have been found to demonstrate an increased propensity for tumor formation upon loss of<unk>  function.<unk>  disruption occurs in a wide variety of cancer types, and results in more metastatic tumors, and correspondingly poorer prognoses. It is thought that, beyond the importance it plays in apoptotic roles,<unk>  inactivation may cause cells to favor tumor progression by allowing the cell to accumulate additional genetic damage. Many proteins involved in genomic stability maintenance rely on the<unk> -NBs for targeting, and<unk>  loss thus leads to a decrease in repair efficiency within the cell. Cell Cycle Role<unk> -NB distribution and concentration changes as the cell moves through the cell cycle. In G0 phase, few sumoylated<unk> -NBs are present, but their numbers increase as the cell progresses through G1 to S to G2 stages. During the chromatin condensation occurring during mitosis, the desumoylation of<unk>  causes the dissociation of many associated factors, and the<unk>  proteins self aggregate to form a few, large, aggregates termed mitotic accumulations of<unk>  proteins (MAPPs). In addition to changes in numbers,<unk> -NBs also associate with different proteins over the lifetime of the cycle, and undergo significant biochemical changes in composition. During the S phase of the cell cycle,<unk> -NB complexes break apart as their chromatin scaffold changes during replication. The physical breaking of the<unk> -NBs into smaller fragments promotes the creation of more<unk> -NBs that exist in G2, however, the expression levels of the<unk>  protein hasn't increased. It is thought that this may serve to preserve the orientation of the chromatids with which the<unk> -NBs are associated, or monitor the integrity of replication forks. Antiviral functions Transcription of<unk>  is increased by the presence of interferon α/β and γ. It is thought that the increased numbers of<unk> -NBs that result from this increase in expression of the<unk>  protein may result in the sequestering of viral proteins in the<unk> -NBs. Thus, the virus is unable to make use of them. The proteins held by<unk> -NBs are then sumoylated, inactivating the virions permanently.
Promyelocytic leukemia protein
Myeloma protein
Tumor-associated glycoprotein 72
Retinoblastoma protein
Lymphocyte function-associated antigen 1
Mammaglobin
Interferon-induced transmembrane protein 5
Leukemia inhibitory factor