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In eukaryotes, the protein kinase Ataxia-Telangiectasia and Rad3-related (ATR), a member of the phosphatidylinositol 3-kinase-like family, acts as a master regulator of the eukaryotic response to DNA injuries, ensuring DNA replication completion and genome stability. Here we aimed to investigate the functional relevance of the ATR homolog in the DNA metabolism of\n                    <jats:italic>Leishmania major<\/jats:italic>\n                    , a protozoan parasite with a remarkably plastic genome. CRISPR\/cas9 genome editing was used to generate a Myc-tagged ATR cell line (mycATR), and a Myc-tagged C-terminal knockout of ATR (mycATR\u0394C-\/-). We show that the nuclear localisation of ATR depends upon its C-terminus. Moreover, its deletion results in single-stranded DNA accumulation, impaired cell cycle control, increased levels of DNA damage, and delayed DNA replication re-start after replication stress. In addition, we show that ATR plays a key role in maintaining\n                    <jats:italic>L. major\u2019s<\/jats:italic>\n                    unusual DNA replication program, where larger chromosomes duplicate later than smaller chromosomes. Our data reveals loss of the ATR C-terminus promotes the accumulation of DNA replication signal around replicative stress fragile sites, which are enriched in larger chromosomes. Finally, we show that these alterations to the DNA replication program promote chromosome instability. In summary, our work shows that ATR acts to modulate DNA replication timing, limiting the plasticity of the\n                    <jats:italic>Leishmania<\/jats:italic>\n                    genome.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011899","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T18:32:43Z","timestamp":1764009163000},"page":"e1011899","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["ATR, a DNA damage kinase, modulates DNA replication timing in Leishmania major"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3114-2314","authenticated-orcid":true,"given":"Gabriel L. A.","family":"da Silva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2077-3214","authenticated-orcid":true,"given":"Jeziel D.","family":"Damasceno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Black","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Lapsley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5739-976X","authenticated-orcid":true,"given":"Richard","family":"McCulloch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz R. O.","family":"Tosi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"issue":"2","key":"pgen.1011899.ref001","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.molcel.2010.09.019","article-title":"The DNA damage response: making it safe to play with knives","volume":"40","author":"A Ciccia","year":"2010","journal-title":"Mol Cell"},{"issue":"7267","key":"pgen.1011899.ref002","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/nature08467","article-title":"The DNA-damage response in human biology and disease","volume":"461","author":"SP Jackson","year":"2009","journal-title":"Nature"},{"issue":"6","key":"pgen.1011899.ref003","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.molcel.2017.05.015","article-title":"ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response","volume":"66","author":"AN Blackford","year":"2017","journal-title":"Mol Cell"},{"key":"pgen.1011899.ref004","doi-asserted-by":"crossref","first-page":"103524","DOI":"10.1016\/j.dnarep.2023.103524","article-title":"Compartmentalization of the DNA damage response: Mechanisms and functions","volume":"128","author":"E Alghoul","year":"2023","journal-title":"DNA Repair (Amst)"},{"key":"pgen.1011899.ref005","article-title":"Exo1 and DNA2-mediated ssDNA gap expansion is essential for ATR activation and to maintain viability in BRCA1-deficient cells","author":"N Garc\u00eda-Rodr\u00edguez","year":"2024","journal-title":"Nucleic Acids Research"},{"key":"pgen.1011899.ref006","doi-asserted-by":"crossref","unstructured":"Zou L, Liu D, Elledge SJ, Verna \u00a7, Mclean M. Replication protein A-mediated recruitment and activation of Rad17 complexes. 2003;100.","DOI":"10.1073\/pnas.2336100100"},{"issue":"1","key":"pgen.1011899.ref007","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-023-39579-y","article-title":"ssDNA accessibility of Rad51 is regulated by orchestrating multiple RPA dynamics","volume":"14","author":"J Ding","year":"2023","journal-title":"Nat Commun"},{"key":"pgen.1011899.ref008","unstructured":"Cortez D, Guntuku S, Qin J, Elledge SJ. ATR and ATRIP: Partners in Checkpoint Signaling [Internet]. 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