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mei-MCM: The Anti-Anti-Crossover Complex

During mitotic DSB repair, helicases act to prevent crossovers. During meiotic DSB repair, crossovers must be generated to promote chromosome segregation. However, these anti-crossover helicases are present and active, so there needs to be some mechanism to block their activities: an anti-anti-crossover. In many eukaryotes, the anti-anti-crossover activity is provided by the Msh4-Msh5 heterodimer.

Curiously, higher flies (Schizophora and other Muscomorpha) have lost Msh4 and Msh5. We have hypothesized that a complex of MCM proteins took over this job.

REC (MCM8) is a mei-MCM

Mutations in the recombination defective (rec) gene were isolated by Rhoda Grell (1978) based on a severe decrease in meiotic crossing over (Grell 1978). We cloned the gene and found that it encodes the Drosophila ortholog of MCM8 (Blanton et al., 2005). Eukaryotic genomes encode six paralogous mini-chromosome maintenance proteins, MCM2-MCM7, that function together in replication fork licensing and as the replicative helicase.

MCM8 and MCM9 are found in many plants, protists, and animals, but have been lost from nematodes, most fungi, and some other lineages. In almost all species examined, there are orthologs of MCM8 and MCM9 or both are absent, suggesting the function together. The exception is higher flies, which have lost MCM9. Furthermore, has evolved under positive selection in the branch that separates higher flies from Nematocera (the sub-order of Diptera that includes mosquitoes, midges, and other flies), suggesting it acquired a new function.

H. Blanton, S.J. Radford, H. Kearney, S. McMahan, J. Ibrahim, and J. Sekelsky (2005) REC, Drosophila MCM8, drives formation of meiotic crossovers. PLoS Genetics 1: e40.

MEI-217 and MEI218: An Ancient MCM-related Protein

We placed rec into a class of genes called "pre-condition", because their products were thought to be required for establishing conditions necessary for crossovers to form (Baker & Carpenter 1972). If we restrict the definition to include only null phenotypes, then the only other genes in this class are mei-217 and mei-218. MEI-217 and MEI-218 are translated as overlapping ORFs from the same transcript (Liu 2000).

MEI-217 and MEI-218 were initially described as "pioneer proteins," meaning they weren't similar to any known proteins. We used PHYRE, which compares consensus 2° structure prediction and 1° sequence to structure databases, to show that MEI-217 is shaped like the N-terminal MCM domain and MEI-218 has a C-terminal MCM-related ATPase-like domain. We then used a combination of yeast two-hybrid and co-IP from insect cell expression to show that MEI-217 interacts with both MEI-218 and REC. We called this the mei-MCM complex.

K. Kohl, C.D. Jones, and J. Sekelsky (2005) Evolution of an MCM complex in flies that promotes meiotic crossovers by blocking BLM helicase. Science 338: 1363-1365.