R-loops acted on by RNase H1 influence DNA replication timing and genome stability in Leishmania
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 comple...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56785-y |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861782039494656 |
|---|---|
| author | Jeziel D. Damasceno Emma M. Briggs Marija Krasilnikova Catarina A. Marques Craig Lapsley Richard McCulloch |
| author_facet | Jeziel D. Damasceno Emma M. Briggs Marija Krasilnikova Catarina A. Marques Craig Lapsley Richard McCulloch |
| author_sort | Jeziel D. Damasceno |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-13a836861e9441e8a379f2c103c38288 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-13a836861e9441e8a379f2c103c382882025-02-09T12:44:18ZengNature PortfolioNature Communications2041-17232025-02-0116112010.1038/s41467-025-56785-yR-loops acted on by RNase H1 influence DNA replication timing and genome stability in LeishmaniaJeziel D. Damasceno0Emma M. Briggs1Marija Krasilnikova2Catarina A. Marques3Craig Lapsley4Richard McCulloch5The University of Glasgow Centre for Parasitology, The Wellcome Centre for Integrative Parasitology, University of Glasgow, School of Infection and Immunity, Sir Graeme Davies Building, 120 University PlaceUniversity of Edinburgh, Institute for Immunology and Infection Research, School of Biological SciencesThe University of Glasgow Centre for Parasitology, The Wellcome Centre for Integrative Parasitology, University of Glasgow, School of Infection and Immunity, Sir Graeme Davies Building, 120 University PlaceThe University of Glasgow Centre for Parasitology, The Wellcome Centre for Integrative Parasitology, University of Glasgow, School of Infection and Immunity, Sir Graeme Davies Building, 120 University PlaceThe University of Glasgow Centre for Parasitology, The Wellcome Centre for Integrative Parasitology, University of Glasgow, School of Infection and Immunity, Sir Graeme Davies Building, 120 University PlaceThe University of Glasgow Centre for Parasitology, The Wellcome Centre for Integrative Parasitology, University of Glasgow, School of Infection and Immunity, Sir Graeme Davies Building, 120 University PlaceAbstract 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.https://doi.org/10.1038/s41467-025-56785-y |
| spellingShingle | Jeziel D. Damasceno Emma M. Briggs Marija Krasilnikova Catarina A. Marques Craig Lapsley Richard McCulloch R-loops acted on by RNase H1 influence DNA replication timing and genome stability in Leishmania Nature Communications |
| title | R-loops acted on by RNase H1 influence DNA replication timing and genome stability in Leishmania |
| title_full | R-loops acted on by RNase H1 influence DNA replication timing and genome stability in Leishmania |
| title_fullStr | R-loops acted on by RNase H1 influence DNA replication timing and genome stability in Leishmania |
| title_full_unstemmed | R-loops acted on by RNase H1 influence DNA replication timing and genome stability in Leishmania |
| title_short | R-loops acted on by RNase H1 influence DNA replication timing and genome stability in Leishmania |
| title_sort | r loops acted on by rnase h1 influence dna replication timing and genome stability in leishmania |
| url | https://doi.org/10.1038/s41467-025-56785-y |
| work_keys_str_mv | AT jezielddamasceno rloopsactedonbyrnaseh1influencednareplicationtimingandgenomestabilityinleishmania AT emmambriggs rloopsactedonbyrnaseh1influencednareplicationtimingandgenomestabilityinleishmania AT marijakrasilnikova rloopsactedonbyrnaseh1influencednareplicationtimingandgenomestabilityinleishmania AT catarinaamarques rloopsactedonbyrnaseh1influencednareplicationtimingandgenomestabilityinleishmania AT craiglapsley rloopsactedonbyrnaseh1influencednareplicationtimingandgenomestabilityinleishmania AT richardmcculloch rloopsactedonbyrnaseh1influencednareplicationtimingandgenomestabilityinleishmania |