Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging.

Formaldehyde (FA) is a recognized environmental and metabolic toxin implicated in cancer development and aging. Inherited mutations in the FA-detoxifying enzymes ADH5 and ALDH2 genes lead to FA overload in the severe multisystem AMeD syndrome. FA accumulation causes genome damage including DNA-protein-, inter- and intra-strand crosslinks and oxidative lesions. However, the influence of distinct DNA repair systems on organismal FA resistance remains elusive. We have here investigated the consequence of a range of DNA repair mutants in a model of endogenous FA overload generated by downregulating the orthologs of human ADH5 and ALDH2 in C. elegans. We have focused on the distinct components of nucleotide excision repair (NER) during developmental growth, reproduction and aging. Our results reveal three distinct modes of repair of FA-induced DNA damage: Transcription-coupled repair (TCR) operating NER-independently during developmental growth or through NER during adulthood, and, in concert with global-genome (GG-) NER, in the germline and early embryonic development. Additionally, we show that the Cockayne syndrome B (CSB) factor is involved in the resolution of FA-induced DNA-protein crosslinks, and that the antioxidant and FA quencher N-acetyl-l-cysteine (NAC) reverses the sensitivity of detoxification and DNA repair defects during development, suggesting a therapeutic intervention to revert FA-pathogenic consequences.

The p53 network: cellular and systemic DNA damage responses in cancer and aging.

The tumor protein TP53 gene, encoding the cellular tumor antigen p53, is the single most frequently mutated gene in human cancers. p53 plays a central role in responding to DNA damage and determines the outcome of the DNA damage checkpoint response by regulating cell cycle arrest and apoptosis. As a consequence of this function, dysfunctional p53 results in cells that, despite a damaged genome, continue to proliferate thus fueling malignant transformation. New insights have recently been gained into the complexity of the p53 regulation of the DNA damage response (DDR) and how it impacts a wide variety of cellular processes. In addition to cell-autonomous signaling mechanisms, non-cell-autonomous regulatory inputs influence p53 activity, which in turn can have systemic consequences on the organism. New inroads have also been made toward therapeutic targeting of p53 that for a long time has been anticipated.