Ring chromosomes are known for a number of unique properties, including mitotic and meiotic instability, and dominant lethality. There is substantial cytological support for an underlying mechanism of chromatin bridging as the cause of these phenomena. Sister chromatid exchange and sister chromatid union have been proposed as mechanisms to produce chromatin bridges that may lead either to chromosome loss or lethality.
We constructed new ring XY chromosomes that produce strong dominant embryonic lethality. These ring chromosomes produce very few gynandromorphs, suggesting that the mechanism that causes dominant lethality is different than the mechanism that produces gynandromorphs. To determine the nature of the lethal mechanism, we investigated whether the canonical DNA damage response is responsible for embryonic death of zygotes with a ring chromosome. By crossing ring XY males to lok (encoding Chk2) or p53 homozygous females we found that both maternal genotypes are able to strongly rescue viability of progeny that inherit the ring chromosome.
Rescue by lok or by p53 differs significantly in that lok mutant mothers produce gynandromorph offspring, while p53 mothers do not. This further suggests that the ring chromosome loss and ring chromosome dominant lethality have distinct causes, and that Chk2 and P53 respond to distinct chromosome abnormalities. Chk2 may normally detect aberrant behavior that would otherwise lead to chromosome loss, while P53 may detect chromosome breakage events. In wildtype embryos, both events would evoke checkpoints that result in lethality, but in mutants, distinct outcomes can be detected. We are continuing to investigate the nature of lok and p53 rescue.