Draft:Positive coactivator 4

PC4 ,also known as p15, is a transcriptional coactivator and an evolutionarily conserved chromatin associated protein.It is encoded by SUB1 gene in humans and was discovered from the upstream stimulatory activator fraction of class II genes , hence named as Positive Coactivator (PC4).PC4 binds dsDNA(Double stranded DNA), ssDNA(Single stranded DNA) , RNA and interacts with many proteins involved in transcription machinery, replication machinery, DNA repair machinery, heterochromatin dynamics etc.

PC4 plays diverse roles in cellular context which include transcriptional coactivation, DNA damage repair, chromatin compaction, autophagy , cell cycle progression, and neurogenesis. The absence of PC4 leads to dramatic chromatin decompaction and altered epigenetic landscape.

Structure

PC4 has an unstructured N-terminal domain (1-62 residues) and a highly structured C-terminal domain (62-127 residues). There are two Serine rich Acidic domains (SEAC) separated by Lysine rich domains (LYS). SEAC domains have the double stranded DNA binding ability which overlaps with its coactivation domain and the C-terminal domain possess the single stranded DNA binding ability and the dimerization domain. The residues 22-87 have the double stranded DNA binding ability which overlaps with its coactivation domain and residues 63-127 possess the single stranded DNA binding ability and the dimerization domain. The N-terminal domain is subjected to different posttranslational modifications in the SEAC as wells as lysine rich domain.

Background

Multifunctional non-histone chromatin protein PC4 (Positive Coactivator 4)

The eukaryotic genome is organized into a dynamic nucleoprotein filament, chromatin. The chromatin structure and function are much more diverse and complex than it was initially revealed. Besides histones, linker histones, and DNA, many more non-histone proteins and RNA are directly involved in the functional organization of the chromatin. The beads on a string nucleosome filament further fold into different domains to regulate underlined gene function, replication, and also repair. Professor Tapas Kundu`s group discovered that highly abundant nuclear protein positive coactivator 4 (PC4) is a bona fide non histone chromatin protein, which compacts the chromatin into a globular structure interacting with core histone and linker histones in a phosphorylation-dependent manner. It interacts with the heterochromatin protein HP1α and preferably stabilizes the heterochromatin organization. Knocking down of PC4 dramatically opens up the chromatin organization, as revealed by micrococcal nuclease digestion and electron microscopy. Furthermore, in the absence of PC4, the global epigenetic landscape changes significantly, resulting activation of autophagy and DNA damage. They found that though PC4 knock-out mice are embryonically lethal, the brain-specific knock-out mice survive with minimal defects in neurogenesis and memory extinction. However, the spleen-specific knockout of PC4 results in a reduced response to antigen stimulation. It also reveals that PC4 maintains B Cell function by regulating gene expression with IKAROS. Therefore, PC4 could be a therapeutic target in human B Cell lymphoma and myeloma cells.

The functional diversity of PC4 is regulated by different post translational modifications. The p300 mediated acetylation of PC4 is critical for its coactivator function, where as the TiP60 mediated acetylation regulates its DNA repair activity. The majority of nuclear PC4 (almost 95%) is a non histone chromatin protein and is phosphorylated. The Casein Kinase II mediated phosphorylation of PC4 is important for chromatin compaction, whereas Aurora kinase mediated phosphorylation aids in spindle assembly and cytokinesis events of cell cycle. In addition to acetylation and phosphorylation, PC4 also gets ubiquitinated by TRIM28 which is also important for cell cycle progression (G1/S transition).

PC4 is downregulated in most breast cancer, causing hyper autophagy and radiation resistance, whereas it is over-expressed and hyper regulated in tobacco-related oral cancer, which upregulates many oncogenes.