Transcriptionally Driven DNA Replication Program of the Human Parasite Leishmania major

• L. major DNA replication origins and nucleosome occupancies are mapped at high resolution
• Those datasets are integrated with mRNA profiling and epigenetic marks
• Nucleosome patterns recapitulate RNA polymerase kinetics
• DNA replication initiates at sites of RNA polymerase pausing and termination

SummaryFaithful inheritance of eukaryotic genomes requires the orchestrated activation of multiple DNA replication origins (ORIs). Although origin firing is mechanistically conserved, how origins are specified and selected for activation varies across different model systems. Here, we provide a complete analysis of the nucleosomal landscape and replication program of the human parasite Leishmania major, building on a better evolutionary understanding of replication organization in Eukarya. We found that active transcription is a driving force for the nucleosomal organization of the L. major genome and that both the spatial and the temporal program of DNA replication can be explained as associated to RNA polymerase kinetics. This simple scenario likely provides flexibility and robustness to deal with the environmental changes that impose alterations in the genetic programs during parasitic life cycle stages. Our findings also suggest that coupling replication initiation to transcription elongation could be an ancient solution used by eukaryotic cells for origin maintenance.

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