PARENT SESSION
MINISYMPOSIUM V. Sexual Dimorphism in Meiosis: Lessons from Genetic Models.
11:00 AM-12:30 PM
Harborside E
Chair: Dekel, Nava¹, ¹

(M13) SEXUALLY DIMORPHIC CHECKPOINT RESPONSES IN MOUSE MEIOTIC RECOMBINATION MUTANTS.

Keeney, Scott¹, DiGiacomo, Monica¹, Baudat, Frédéric², Kolesnick, Richard³, Jasin, Maria², ¹ Molecular Biology Program, New York, NY² Cell Biology Program, New York, NY³ Laboratory of Signal Transduction, New York, NY

ABSTRACT- Meiotic cells monitor the progress of homologous recombination, presumably to coordinate it with other events in meiotic prophase and to prevent attempts to segregate damaged chromosomes. We have explored this monitoring process in the mouse, where recombination failure causes arrest and apoptosis of meiotic cells. The time of arrest not only depended on the molecular nature of the recombination defect, but also showed significant differences between males and females. For example, mutation of the Spo11 gene prevents formation of the DNA double-strand breaks (DSBs) that initiate recombination, whereas mutation of the strand exchange protein Dmc1 blocks the repair of DSBs once they are formed. In males, both mutations caused arrest and apoptosis at late zygonema or early pachynema. Because both mutations caused the same apoptotic response, and because Spo11^-/- mutants were unable to form the DSBs that initate recombination and thus did not accumulate unrepaired DNA damage, we infer that this response in spermatocytes is DNA damage independent. In females, the mutant oocytes progressed further, to at least the diplotene stage. Dmc1 mutant oocytes were then completely eliminated perinatally, but a significant number of Spo11 mutant oocytes escaped this arrest point: they formed follicles, could ovulate, and attempted to carry out meiotic divisions which failed because chromosomes were completely achiasmate. These differences suggest that there are distinct DNA damage dependent and DNA damage independent responses to recombination defects in oocytes. Consistent with this idea, we found that the Spo11 mutation was epistatic to the Dmc1 mutation in oocytes. We are characterizing further the genetic control of the checkpoint and apoptotic responses of recombination-defective meiocytes, focusing our attention initially on the role of p53 and the pro-apoptotic factor acid sphingomyelinase.

KEY WORDS: Meiosis, Recombination, Apoptosis, DNA damage checkpoint