Mu2 cooperates with p53 to regulate fusion of dysfunctional telomeres in Drosophila. Sarah R. Oikemus, Hannah Pham, Michael Brodsky. Dept PGF&E, Univ Massachusetts, Worcester, Worcester, MA.

   p53 plays a conserved role in animals linking the canonical DNA damage response pathway to the cellular machinery that regulates apoptosis, cell cycle control and DNA repair. Animals homozygous for mutations in the ATM homolog, telomere fusion exhibit defective telomere protection, leading to chromosome fusions and p53-dependent apoptosis. We find that p53 promotes non-homologous end-joining (NHEJ) of dysfunctional telomeres and DNA breaks. Genetic analysis demonstrates that p53 specifically regulates DNA repair choice, only promoting NHEJ when homologous recombination (HR) is available as an alternative repair pathway.
   Similar to p53, mu2, the Drosophila ortholog of MDC1 (mediator of DNA damage checkpoint 1), also promotes fusion of unprotected telomeres. Simultaneous loss of both mu2 and p53 does not have an additive effect suggesting that they act in the same pathway to promote telomere fusions. Analysis of the repair products from endonuclease-induced DNA breaks indicates that loss of mu2 affects three repair pathways, NHEJ, HR and single strand annealing. Again similar to p53, mu2 only affects repair when HR is available, suggesting a role in DNA repair pathway choice. A previous large-scale screen identified Mu2 as a potential p53 interacting protein. Using an in vitro pull down assay, we have mapped the interaction sites to the BRCT repeat domain of Mu2 and the N-terminal activation domain of p53. in vivo, we find that Mu2 specifically localizes to unprotected telomeres. We propose that Mu2 acts to recruit p53 to dysfunctional telomeres and DNA breaks and that this interaction helps to regulate DNA repair choice.