DNA repair during organogenesis

Abstract

DNA damage caused by genotoxic agents can impact on virtually any cellular process due to its ability to affect gene expression and subsequent gene products. The importance of repairing damaged DNA is evidenced by the variety of DNA repair pathways that have evolved in all living organisms, and the human syndromes caused by a lack of this repair ability. This review focuses on the expression and activity of DNA repair pathways during mammalian organogenesis, and the role of these pathways in ensuring the stability of the conceptal genome. DNA repair capacity may play a role also in the response of the conceptus to genotoxic agents that may induce malformations; the consequences of exposure to a genotoxic agent during organogenesis depend on the extent of the damage and on the ability of the embryo to respond by repairing DNA or arresting cell division. The four main repair pathways (nucleotide excision repair, base excision repair, mismatch repair, and recombination repair) are expressed to various degrees during organogenesis, as are members of the genotoxic stress-activated cell cycle checkpoint pathways. Developmental-stage-specific alterations in transcript levels, protein levels, as well as activity, indicate that the regulation of DNA repair pathways during development is complex. The importance of DNA repair pathways in endogenous damage control is illustrated by the sensitivity of development to their disruption if some of these genes are mutated. Furthermore, the conceptus has a limited capacity to alter DNA repair responses following exposure to genotoxic agents.