Deregulated macromolecular homeostasis
Once genes are successfully transcribed, the resulting RNA can be modified via alternative splicing to generate multiple protein variants which may have different cellular functions or properties. When RNA is decoded to proteins, translational infidelity promotes protein errors which may result in dysfunctional proteins. Along with defects in protein folding or other damages to the protein structure, protein stress response pathways such as the unfolded protein response or the heat shock response are being activated to initiate refolding or removal of damaged proteins and avoid accumulation of harmful aggregates. Various mechanisms have evolved to degrade dysfunctional macromolecules and organelles, via the ubiquitin proteasome system or the autophagy lysosomal pathway.
Epigenetic modifications
Each cell in an organism contains the exact same genome, yet can possess vastly different properties and perform vastly different functions. This is possible because the DNA is coiled around histone proteins into a secondary structure, called chromatin, which serves to condense the genomic DNA and control its transcription. Regulation of chromatin through modifications like DNA methylation or histone acetylation is therefore critical for gene expression, and changes in chromatin structure can result transcriptional defects.
Genome instability
The genome is organized in chromosomes which carry the information required to build a functional organism, encoded in its DNA. Various stresses, like radiation and free radicals can lead to physical alterations in DNA structure, such as breaks, crosslinks, and other modifications, and several sophisticated mechanisms have evolved to repair such damage. During cell division, a copy of the entire genome is generated and any remaining damage can increase the risk for errors in the DNA replication process. These errors can comprise single point mutations in the genetic code, but also include chromosomal aberrations, transpositions and copy number variation. In addition, the ends of chromosomes are protected by structures called telomeres, which also get damaged and eroded with each cell division.
