DNA damage signaling in early Xenopus embryos.

In Xenopus embryos, the first 12 cell division cycles before the midblastula transition (MBT) feature rapid and synchronous alternations between DNA replication and mitosis. Moreover, embryos at this stage lack checkpoints that halt the cell cycle in response to DNA damage, whereas introduction of a threshold amount of undamaged plasmid or sperm DNA allows a DNA damage checkpoint response to be activated. In a search for the underlying mechanism, we recently discovered that the checkpoint signal initiated by damaged DNA is enhanced by the undamaged threshold DNA. Thus developmental regulation of the cell cycle checkpoint is achieved at the 12(th) cleavage divisions by the maternally programmed increase in the DNA-to-cytoplasmic ratio. In contrast, the apoptotic response to DNA damage is not enabled in pre-MBT embryos merely by providing a threshold DNA-to-cytoplasmic ratio. Interestingly, damaged DNA triggers changes on physically separated undamaged chromatin through release of an ATM-dependent soluble checkpoint signal. We propose that this novel mode of "in trans" regulation is employed in the DNA damage response to modulate a broad range of chromatin-associated activities in a genome-wide manner.