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Extrachromosomal DNA amplification is frequent in the protozoan parasite  Leishmania  selected for drug resistance. The extrachromosomal amplified DNA is either circular or linear, and is formed at the level of direct or inverted homologous repeated sequences that abound in the  Leishmania  genome. The RAD51 recombinase plays an important role in circular amplicons formation, but the mechanism by which linear amplicons are formed is unknown. We hypothesized that the  Leishmania infantum  DNA repair protein MRE11 is required for linear amplicons following rearrangements at the level of inverted repeats. The purified LiMRE11 protein showed both DNA binding and exonuclease activities. Inactivation of the  LiMRE11  gene led to parasites with enhanced sensitivity to DNA damaging agents. The MRE11 −/−  parasites had a reduced capacity to form linear amplicons after drug selection, and the reintroduction of an  MRE11  allele led to parasites regaining their capacity to generate linear amplicons, but only when MRE11 had an active nuclease activity. These results highlight a novel MRE11-dependent pathway used by  Leishmania  to amplify portions of its genome to respond to a changing environment.

Formation of Linear Amplicons with Inverted Duplications in Leishmania Requires the MRE11 Nuclease