A novel mode for regulation of translesion DNA polymerases in early C. elegans embryos

Much of what we have learned about DNA damage response pathways has come from the study of homogenous populations of cells growing in culture, namely yeasts and mammalian tissue culture cells. Although these systems have been extremely informative in describing how individual DNA damage response pathways function, they are by their nature unable to lend insight into how these pathways interact with one another in the context of multi‐cellular organisms, and during different phases of animal development. We have been studying how early C. elegans embryos respond to DNA damage, and the results have revealed insights that were unexpected based on paradigms established by studies on cultured cells. Specifically, we have found that early embryos actively suppress activation of the ATR‐dependent checkpoint during a DNA damage response. To do so, embryos employ a robust capacity for translesion DNA synthesis, an inherently mutagenic process, so that replication is not slowed, even when chromosomes are heavily damaged. We have also discovered a novel regulatory system that limits the amount of DNA that is replicated by translesion DNA polymerases during a damage response. Our results suggest that translesion synthesis assumes an unusually prominent role during an early embryonic DNA damage response, and that to buffer themselves against the deleterious consequences of translesion synthesis, embryos have evolved a regulatory system that limits replication by these mutagenic polymerases. In a more general sense, our results suggest that continued study of DNA damage response pathways in multi‐ and heterogeneous cell systems will uncover further surprises and examples where the “rule book” seems to have been discarded.