Attack of Progerin:
“Lamins are intermediate filament proteins forming a network in the inner nuclear membrane” (ubcmj.com). They are essential to the body, "maintaining the structural integrity of the nucleus" and have a hand in chromatin organization, DNA replication/transcription, and RNA processing (ubcmj.com). A common malfunction that occurs in HGPS patients is a heterozygous single cytosine to thymine point mutation in exon 11 at position 1824 of the coding sequence. Although there is no amino acid change, such mutation "generates a cryptic splice site, resulting in a transcript 150 base pairs shorter than normal and 50 fewer amino acids translated" within the prelamin A protein (ubcmj.com). The underlying problem of this mutation is that necessary zinc metalloprotease (Zmpste24) cleavage sites are present in the 50 amino acids that were not translated. The Zmpste24 protein is an integral component of prelamin A maturation; it cuts immature prelamin A at two particular sites. The Zmpste24 gene in return provides instructions for making a protein that acts as a protease (an enzyme that cuts (cleaves) other proteins). Thus, farnesylated prelamin A anchors to the nuclear envelope. Failure to cleave the prelamin A results in the formation and accumulation of "smaller farnesylated and carboxy-methylated mutant prelamin A protein," also known as progerin, in the nuclear envelope (impactaging.com). The hydrophobic farnesyl chain gives progerin a higher affinity for the inner nuclear membrane, which redistributes progerin away from nucleoplasmic foci; this association deforms the membrane. The integrity of the nucleus is ultimately disrupted, resulting in nuclei that appear "larger, distorted, blebbed, and have a thicker nuclear lamina" (ubcmj.com). "The mechanical properties of the nuclear lamina in HGPS cells are compromised. The nuclei are stiffer, have reduced deformability, and do not respond to mechanical force in the same manner as normal cells" (ubcmj.com). Cell proliferation, differentiation, and gene expression are therefore altered in HGPS cells. These deficiencies in the basic cellular processes affect surrounding tissues such as the skin, bone, and cardiovascular tissues (ubcmj.com).
Normal Process of Lamin A Maturation:
Normally, the lamin A mRNA is translated to prelamin A and becomes farnesylated. As a result, the farnesylated prelaim A anchors to the inner nuclear membrane and is cleaved by Zmpste24, which produces mature lamin A.
Damages Inflicted on Genome Replication:
During interphase, there is a loss of heterochomatin and nucleoplasmic lamin A foci. The nucleoplasmic foci contain replicative proteins (PCNA and polymerase), which are critical for ordered initiation of genome replication in early S phase (impactaging). DNA replication occurs during the S phase, the phase of DNA synthesis. During the S phase, a "checkpoint" is triggered when problems with DNA replication are encountered. Checkpoints serve as...