Meiosis promotes diversity within a population through crossover recombination. In fact, failure to execute recombination, through improper orchestration of double strand break (DSB) formation or repair, homologous chromosome pairing, or synapsis, can result in nondisjunction (NDJ), the erroneous segregation of chromosomes into gametes. With few exceptions, NDJ results in fatal outcomes accounting for ~50% of spontaneous abortions. While study of meiosis is extremely difficult in mammalian systems, it is specifically suited for study in C. elegans due to the fact that NDJ of the X chromosome leads to increased production of males, a completely viable outcome. The High Incidence of Males, or Him phenotype, has been used to identify and characterize nondisjunction mutants including the
him-5 locus described here.
The initial characterization of
him-5 by Jonathan Hodgkin revealed an X chromosome bias for
him-5, with approximately 40% male self-progeny (compared to 0.2% in wild type) and high viability (indicating normal segregation of autosomes). Our characterization of
him-5 has revealed that it is required for DSB formation on the X, in some if not all nuclei. In addition, DSB formation on autosomes is also somewhat compromised in the mutant and appears to be exacerbated by age. Cytological analysis of
him-5 reveals a delay in meiotic progression, which can be rescued through induction of exogenous DSBs via irradiation, suggesting an active mechanism to monitor crossover exchange intermediates.
Through our studies we have also discovered redundant roles for
him-5 and
cep-1, the C. elegans
p53 homologue, in DNA damage repair.
him-5;
cep-1 double mutants have significant embryonic lethality. These arise due to defects in meiosis as seen by analysis of diakinesis nuclei where
cep-1;
him-5 mutants display Rad-51-like chromosomal fusions. Our more detailed characterization of these double mutants will be presented along with a framework to understand the role of these genes in DNA damage repair.