We study mechanisms and regulation of genetic recombination. Recombination is merely any exchange of DNA information, usually in the form of reciprocal crossing over or unidirectional gene conversion. The origins, outcomes, and consequences of recombination are different in different contexts.
In the case of meiotic recombination, DNA double-strand breaks (DSBs) are induced to promote high rates of crossing over between homologous chromosomes. These crossovers provide physical links that allow the homologs to align on the metaphase meitoic spindle in an orientation that guides proper disjunction. Defects in meiotic recombination result in aneuploidy or sterility. Meiotic crossovers also increases diversity among offspring by allowing different alleles from linked genes to be put together in new combinations.
In contrast, mitotic recombination is usually an abnormal process. In mitotically proliferating cells, DSBs result from potentially harmful events like exposure to ionizing radiation, problems encountered during DNA replication, and excision of DNA transposable elements. Even when DSBs do occur, repair is usually biased to prevent crossover formation. Crossovers that do occur can have adverse effects, including loss of heterozygosity or chromosome rearragements (for recombination between non-allelic sequences), both of which are associated with tumorigenesis.
These differences lead to a key question that runs through much of our research:
and to prevent crossovers in other cells?
To address this question, we study the roles of three protein classes:
- anti-crossover helicases: BLM, FANCM, and RTEL
- pro-crossover resolvases: mei-HEM, GEN, MUS81-MMS4, and MUS312-SLX1
- anti-anti-crossover proteins: the mei-MCM complex
We primarily use genetic approaches, using Drosophila melanogaster as a model. More recently, we have take additional approaches (biochemistry, cell biology, computational biology, etc.) and additional models (fission yeast, budding yeast, and human cells).