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Lookup NU author(s): Dr Emma BriggsORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Genomes in eukaryotes normally undergo DNA replication in a choreographed temporal order, resulting in early and late replicating chromosome compartments. Leishmania, a human protozoan parasite, displays an unconventional DNA replication program in which the timing of DNA replication completion is chromosome size‑dependent: larger chromosomes complete replication later than smaller ones. Here we show that both R‑loops and RNase H1, a ribonuclease that resolves RNA‑DNA hybrids, accumulate in Leishmania major chromosomes in a pattern that reflects their replication timing. Furthermore, we demonstrate that such differential organisation of R‑loops, RNase H1 and DNA replication timing across the parasite’s chromosomes correlates with size‑dependent differences in chromatin accessibility, G‑quadruplex distribution and sequence content. Using conditional gene excision, we show that loss of RNase H1 leads to transient growth perturbation and permanently abrogates the differences in DNA replication timing across chromosomes, as well as altering levels of aneuploidy and increasing chromosome instability in a size‑dependent manner. This work provides a link between R‑loop homeostasis and DNA replication timing in a eukaryotic parasite and demonstrates that orchestration of DNA replication dictates levels of genome plasticity in Leishmania.
Author(s): Damasceno JD, Briggs EM, Krasilnikova M, Marques CA, Lapsley C, McCulloch R
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2025
Volume: 16
Online publication date: 08/02/2025
Acceptance date: 31/01/2025
Date deposited: 09/04/2026
ISSN (electronic): 2041-1723
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-025-56785-y
DOI: 10.1038/s41467-025-56785-y
Data Access Statement: Sequences used in this study have been deposited in the EMBL-EBI European Nucleotide Archive (ENA) under the accession number PRJEB75366; MFA-seq data is available in the NCBI Sequence Read Archive (SRA) with the accession number PRJNA1108605. Source data are provided with this paper.
PubMed id: 39922816
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