aging and transcription
premature-aging syndromes
Cells from patients with the premature-ageing syndrome Cockayne syndrome have been shown to have defects not only in the recovery of RNA synthesis following UV-light irradiation, but also in general transcription.
It is possible that oxidative damage from endogenous sources causes transcription blocking and that the repair of these blocking lesions and recovery of RNA synthesis requires the Cockayne syndrome factors.
Similarly, premature-ageing phenotypes have been observed in mice that have a specific mutation in XPD, giving rise to another premature-ageing sydrome, trichothiodystrophy (TTD). Xpd codes for a DNA helicase involved in both DNA repair and transcription.
Specifically, lesions blocking transcription, which are linked to the induction of apoptosis, might be responsible for the accelerated-ageing phenotype in TTD. This increased sensitivity of damaged TTD and Cockayne syndrome cells to apoptosis coupled with proficient GGR might explain the low cancer incidence among individuals with these syndromes.
The connection between transcription deficiencies and ageing is not limited to Cockayne syndrome and TTD. In fact, many other premature-ageing syndromes and knockout mice with premature-ageing phenotypes show defects in general transcription.
Cells from the premature-aging syndromes Werner syndrome, Bloom syndrome and Rothmond-Thomson syndrome that have specific defects in RecQ DNA helicase activity, seem to have reduced transcription efficiency compared with cells from normal individuals.
Another premature-ageing syndrome, Hutchinson-Gilford progeria syndrome, was recently shown to be caused by mutations in lamin A/C111, 112, which encodes proteins that form part of a filamentous network in the nuclear envelope.
Interestingly, it has been shown that expression of dominant-negative forms of lamin A significantly reduces transcription by RNA polymerase II, indicating that a transcription deficiency might contribute to the premature-ageing phenotype in Hutchinson- Gilford progeria syndrome.
The Ku86-knockout mouse expresses a premature-ageing phenotype. KU86 (KU80 in humans) is key in initiating a major pathway in repair of DNA double-strand breaks called non-homologous end-joining, but was recently also implicated in the transcription process mediated by RNA polymerase II.
The common feature of these premature-ageing syndromes is that their genetic deficiencies negatively affect RNA polymerase II and therefore promote apoptosis. So, reduced transcription might contribute to the premature-ageing phenotype in these disorders.
Although some of these syndromes, such as Cockayne syndrome and TTD, are associated with a low incidence of cancer, this is not true for all of the premature-ageing syndromes. As some of these syndromes have defects in genes involved in DNA repair and DNA-damage signalling, it is likely that the contributions of these defects to genomic instability outweighs the tumour suppression afforded by an increased apoptotic response.