Active transcriptomic and proteomic reprogramming in theC. elegansnucleotide excision repair mutant xpa-1

Abstract

O xidative stress promotes human aging and contributes to common neurodegenerative diseases. Endogenous DNA damage induced by oxidative stress is believed to be an important promoter of neurodegenerative diseases. Although a large amount of evidence correlates a reduced DNA repair capacity with aging and neurodegenerative disease, there is little direct evidence of causality. Moreover, the contribution of oxidative DNA damage to the aging process is poorly understood. We have used the nematode Caenorhabditis elegans to study the contribution of oxidative DNA damage and repair to aging. C. elegans is particularly well suited to tackle this problem because it has a minimum complexity DNA repair system, which enables us to circumvent the important limitation presented by the extensive redundancy of DNA repair enzymes in mammals. Oxidative DNA Damage and Aging in C. elegansThe free radical theory of aging is an example of a hypothesis that, because it intuitively makes sense, is attractive both to scientists and to the general public. The theory has been enormously influential and has inspired scientists to test its implications ever since its first formulation by Denham Harman. 1 As such it is a good theory because it suggests many testable hypotheses. However, few experiments have provided direct support of the original theory. This has led to the formulation of many offshoots like the mitochondrial theory of aging and the stochastic damage accumulation theory of aging.One prediction that can be made from all of these theories is that oxidative damage to cellular macromolecules contributes to the progressive loss of function associated with aging. As DNA, unlike other cellular macromolecules, cannot be replaced in its entirety, it seems logical that maintenance of genomic stability would promote longevity and limit functional loss during aging.A role for passive and stochastic accumulation of oxidative DNA damage in aging is often dismissed by scientists outside the DNA repair field for three principal reasons; first, even though levels of reactive oxygen species (ROS) increase with age 2,3 and DNA repair capacity diminishes with age, 4 it has been difficult to unequivocally show that oxidative DNA damage accumulates with age. Also, since a plethora of different types of DNA lesions are induced by ROS, it is not entirely clear which types of lesions are more relevant to the aging phenotype. Second, there is no good correlation between mutation accumulation and aging. [5][6][7] Third, mutants that fail to repair oxidative DNA damage show normal lifespan. However, there are technical and biological factors that would explain these observations and further research is needed to determine whether and how oxidative DNA damage contributes to aging. Segmental Progeroid NER SyndromesIt is often overlooked that DNA damage may not only be mutagenic, but also

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+signaling

“…For microarray analysis of nematodes, N2, csa-1, csb-1, csa-1;csb-1 worms were exposed to 500 µM NR from the L4 stage and whole-body tissue was collected at adult day 7 for RNA extraction (Qiagen RNeasy mini kit with a QIAcube machine) [57]. Three biological replicates were prepared for each group.…”