{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:03:11Z","timestamp":1789340591314,"version":"build-2803163510"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>R-loops, three-stranded nucleic acid structures composed of an RNA-DNA hybrid and displaced single-stranded DNA, are tightly regulated by single-stranded DNA-binding proteins. However, the role of lactate dehydrogenase A (LDHA), an atypical DNA-binding protein and key glycolytic enzyme, in R-loop regulation remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cleavage Under Targets and Tagmentation sequencing (CUT&amp;amp;Tag-seq) was utilized to map R-loop and LDHA genomic landscapes in wild-type (WT) and LDHA knockout (KO) 4T1 cells. RNA-seq was employed for transcriptomic profiling. Immunofluorescence was used to evaluate the co-localization of LDHA and R-loops. Western blotting was performed to assess the protein levels of LDHA, RNase H1, and \u03b3-H2AX.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>LDHA knockout disrupted R-loop homeostasis, resulting in altered S9.6-enriched peaks, with 199 peaks increased and 81 decreased in 4T1 cells. Exogenous lactate failed to rescue these R-loop perturbations, suggesting that LDHA regulates R-loops through a mechanism beyond its metabolic activity. Genomic analysis revealed partial overlap between LDHA-binding sites and R-loop-prone regions, indicating a potential direct role of LDHA in R-loop formation. Transcriptomic profiling showed widespread gene expression changes following LDHA loss, although only four genes were associated with both LDHA binding and R-loop peaks. Importantly, LDHA knockout induced accumulation of R-loop foci and DNA damage, both of which were reversed by RNase H1 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings identify LDHA as a novel regulator of R-loops and suggest that it may influence R-loop homeostasis through direct DNA binding rather than solely through its enzymatic role in glycolysis. Further studies are needed to elucidate the molecular mechanism underlying LDHA-mediated R-loop regulation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1942597","type":"journal-article","created":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T22:10:13Z","timestamp":1789337413000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Loss of lactate dehydrogenase A disrupts R-loop homeostasis and induces DNA damage in breast cancer cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Shangzhen","family":"Li","sequence":"first","affiliation":[{"name":"Nanjing Key Laboratory of Hepatology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine","place":["Nanjing, China"]},{"name":"Department of Pharmacy, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuling","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoping","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1016\/j.kint.2023.08.006","article-title":"Abnormal lactate metabolism is linked to albuminuria and kidney injury in diabetic nephropathy","volume":"104","author":"Azushima","year":"2023","journal-title":"Kidney Int."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3707","DOI":"10.1016\/j.molcel.2023.09.021","article-title":"Dicer ribonuclease removes harmful R-Loops","volume":"83","author":"Camino","year":"2023","journal-title":"Mol. 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