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R-loops acted on by RNase H1 influence DNA replication timing and genome stability in Leishmania

Author

Listed:
  • Jeziel D. Damasceno

    (120 University Place)

  • Emma M. Briggs

    (School of Biological Sciences
    Framlington Place)

  • Marija Krasilnikova

    (120 University Place)

  • Catarina A. Marques

    (120 University Place)

  • Craig Lapsley

    (120 University Place)

  • Richard McCulloch

    (120 University Place)

Abstract

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 then 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.

Suggested Citation

  • Jeziel D. Damasceno & Emma M. Briggs & Marija Krasilnikova & Catarina A. Marques & Craig Lapsley & Richard McCulloch, 2025. "R-loops acted on by RNase H1 influence DNA replication timing and genome stability in Leishmania," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56785-y
    DOI: 10.1038/s41467-025-56785-y
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    References listed on IDEAS

    as
    1. Sarah Cohen & Nadine Puget & Yea-Lih Lin & Thomas Clouaire & Marion Aguirrebengoa & Vincent Rocher & Philippe Pasero & Yvan Canitrot & Gaëlle Legube, 2018. "Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    2. Michael B. Heskett & Athanasios E. Vouzas & Leslie G. Smith & Phillip A. Yates & Christopher Boniface & Eric E. Bouhassira & Paul T. Spellman & David M. Gilbert & Mathew J. Thayer, 2022. "Epigenetic control of chromosome-associated lncRNA genes essential for replication and stability," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Benjamin D. Pope & Tyrone Ryba & Vishnu Dileep & Feng Yue & Weisheng Wu & Olgert Denas & Daniel L. Vera & Yanli Wang & R. Scott Hansen & Theresa K. Canfield & Robert E. Thurman & Yong Cheng & Günhan G, 2014. "Topologically associating domains are stable units of replication-timing regulation," Nature, Nature, vol. 515(7527), pages 402-405, November.
    4. Wei-Ting Lu & Ben R. Hawley & George L. Skalka & Robert A. Baldock & Ewan M. Smith & Aldo S. Bader & Michal Malewicz & Felicity Z. Watts & Ania Wilczynska & Martin Bushell, 2018. "Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    5. Britny Blumenfeld & Hagit Masika & Marganit Farago & Yishai Yehuda & Lamia Halaseh & Oriya Vardi & Rachel Rapoport & Rena Levin-Klein & Howard Cedar & Yehudit Bergman & Itamar Simon, 2021. "Chromosomal coordination and differential structure of asynchronous replicating regions," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    6. Konstantina Skourti-Stathaki & Kinga Kamieniarz-Gdula & Nicholas J. Proudfoot, 2014. "R-loops induce repressive chromatin marks over mammalian gene terminators," Nature, Nature, vol. 516(7531), pages 436-439, December.
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