Molecular Mechanisms of Dyskeratosis Congenita
Since dyskerin is the protein mutated in X-linked dyskeratosis congenita, its function is important to understanding DC’s effect on cells. Though the function has not been thoroughly established, it is believed that dyskerin has many important functions throughout the cell cycle; its knockdown disrupts mitosis and triggers the spindle-assembly checkpoint to prevent cell cycle progression (Alawi, 2013). This mitotic disruption could be a result of many different functions and mechanisms, leaving the exact function of dyskerin unknown. In humans, it has been discovered that there are multiple roles for dyskerin; these include ribosomal RNA ...view middle of the document...
Telomerase is only active during the first few weeks of embryonic development and then is permanently shut off, which means the telomere length is determined for the entire life span at once (Cristofari, 2007). In the telomerase complex, dyskerin binds and stabilizes telomerase RNA (TERC) within the complex (Alawi, 2013).
In the human telomerase complex, two molecules of human telomerase reverse transcriptase (TERT), telomerase RNA (TERC) and dyskerin are present. TERT is a reverse transcriptase which creates single-stranded DNA using a single-stranded RNA template. Using TERC, TERT adds the TTAGGG sequence to the 3’ end of chromosomes. TERC contains the template region for elongation and TERT positions this sequence on the end of the telomere (Matsuura, 2011). After the telomerase complex is built it needs to be recruited to the chromosome itself.
The elongation of telomeres begins by replication fork progression; replication is initiated from a replication origin on the chromosome and moves towards the terminus of the same chromosome. The replication fork reaches the terminus and a 3’ overhang is made, which is critical to signal telomerase to the cell. This overhang serves as the DNA template for telomeres while telomerase provides the RNA template (Matsuura, 2011). Once this overhang is completed, telomere proteins are recruited. These telomere proteins assemble and telomerase can then be recruited. Modifications occur allowing binding and permitting telomerase to load on the 3’ overhang. Telomerase then elongates the telomere (Matsuura, 2011). This entire process can be visualized in Figure 3.
A number of RNA binding proteins interact with TERT and TERC to help with stability, maturation, accumulation and assembly of telomerase. The known RNA binding proteins are: GAR, dyskerin, NOP10, NHP2, Stau, L22, nRNP C1/C1, and La. A few of these proteins are seen associated with telomerase in Figure 1. Specific to human telomerase are GAR1, dyskerin, NOP10, and NHP2; all of which have been found to be mutated in different forms of DC (Matsuura, 2011). Dyskerin catalyzes pseudouridylation of rRNA, which is the transformation of a uridine reside to a pseudouridine; this conformational transformation can be seen in Figure 4A. It is believed that the pseudouridine modification of telomerase occurs at a P6.1 loop nucleotide in TERC. When P6.1 is pseudouridylated, there is rearrangement of the loop’s conformation which exposes many loop nucleotides. The exposed nucleotides interact with a template-adjacent region of a pseudoknot domain of TERT, increasing the stability of telomerase (Kim, 2010).
Therefore it can be derived that dyskerin pseudouridylates a domain of TERC that allows for binding to TERT, creating and stabilizing the telomerase complex. Without dyskerin this pseudouridylation does not occur, preventing the formation and stabilization of telomerase. Dyskerin is also believed to provide other functions to telomerase...