Seminar in Biological Mechanisms of Aging and Cancer/Genomic Instability (nuclear architecture)

All the genetic material in a cell/ organism is referred to as the genome. The genome encodes for all the proteins that make up an organism. The genome is stored in the nucleus within a cell. Nuclear lamina is a structural component of the nucleus. Nuclear lamina consists of a group of proteins that together act like the skeleton of the nucleus, which helps the nucleus retain its signature spherical shape. When the synthesis of any component of the nuclear lamina is hindered, the nucleus becomes architecturally unstable resulting in an upregulation of pathways that cause senescence (aging). In this way, an unstable nuclear architecture can be recognized as a part of genomic instability, which is a hallmark of aging. As an example of research that has been done relating to this hallmark of aging, we discussed a paper published by Varela et al. in 2005. The authors studied the effect of an unhealthy nuclear lamina on the p53 pathway (a pathway that results in cell senescence and cell death). They used mice as their model organism. They specifically focused on deficient production of laminA, a key component of nuclear lamina. LaminA synthesis is dependent on two different genes, the lmna gene and the zmpste24 gene. The lmna gene makes premature or pre-laminA. The zmpste24 gene makes a metalloproteinase which then aids in synthesis of mature laminA from the premature form. The scientists found that mice with defective zmpste24 gene experience an upregulation of the p53 pathway and demonstrate some of the key features of senescence. They also found that a reduction in the accumulation of pre-laminA helps downregulate the p53 pathway and eliminate the signs of senescence. Thus they concluded that it is rather the accumulation of pre-laminA, not the lack of mature laminA, that triggers the p53 pathway. Working with mice deficient in the p53 gene allowed the scientists to conclude that the accumulation of pre-laminA most likely triggers other pathways which also accelerate senescence. Below is our attempt to create a graphical abstract summarizing this paper