{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:11:38Z","timestamp":1789153898779,"version":"build-2803163510"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA237286"],"award-info":[{"award-number":["R01CA237286"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA244044"],"award-info":[{"award-number":["R01CA244044"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA244179"],"award-info":[{"award-number":["R01CA244179"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA244707"],"award-info":[{"award-number":["R01CA244707"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA186238"],"award-info":[{"award-number":["R01CA186238"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005189","name":"Leukemia and Lymphoma Society","doi-asserted-by":"publisher","award":["TRP 6628-21"],"award-info":[{"award-number":["TRP 6628-21"]}],"id":[{"id":"10.13039\/100005189","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Normal hematopoietic stem and progenitor cells (HSPCs) are exposed to physiological levels of formaldehyde but occasionally may be challenged by high levels of formaldehyde generated by endogenous and exogenous sources. In addition, leukemia cells stressed by oncogenic mutations continuously produce excessive amounts of formaldehyde. Here, we show that DNA polymerase theta (Pol\u03b8) cooperates with alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 2 (ALDH2) to protect healthy and malignant HSPCs challenged by formaldehyde. ADH5 and ALDH2 metabolize formaldehyde while Pol\u03b8-mediated DNA repair by microhomology-dependent end-joining (TMEJ) protects cells from the lethal effect of DNA double strand breaks resulting from formaldehyde-mediated DNA-protein crosslinks. Genetic or pharmacological targeting of ADH5 or ALDH2 enhanced the effect of Pol\u03b8 inhibitors in leukemic cells. Thus, ADH5\/ALDH2 cooperate with Pol\u03b8 to protect normal HSPCs sporadically challenged by high levels of formaldehyde, and inhibition of Pol\u03b8 and ADH5 or ALDH2 may exert an anti-leukemic effect.<\/jats:p>","DOI":"10.1038\/s41375-025-02687-3","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T12:46:59Z","timestamp":1752151619000},"page":"2152-2162","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["ADH5\/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9563-3358","authenticated-orcid":false,"given":"Jessica","family":"Atkins","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Mariya","family":"Kukuyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8414-253X","authenticated-orcid":false,"given":"Monika","family":"Toma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Drzewiecka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umeshkumar","family":"Vekariya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Karami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Nieborowska-Skorska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Nejati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7409-4204","authenticated-orcid":false,"given":"Emir","family":"Hadzijusufovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0456-5095","authenticated-orcid":false,"given":"Peter","family":"Valent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6918-5056","authenticated-orcid":false,"given":"Tomasz","family":"Stoklosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Sliwinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1988-3670","authenticated-orcid":false,"given":"Mariusz","family":"Wasik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3809-4538","authenticated-orcid":false,"given":"Tomasz","family":"Skorski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,10]]},"reference":[{"key":"2687_CR1","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1002\/em.22087","volume":"58","author":"N Chatterjee","year":"2017","unstructured":"Chatterjee N, Walker GC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen. 2017;58:235\u201363.","journal-title":"Environ Mol Mutagen"},{"key":"2687_CR2","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.molcel.2015.08.020","volume":"60","author":"LB Pontel","year":"2015","unstructured":"Pontel LB, Rosado IV, Burgos-Barragan G, Garaycoechea JI, Yu R, Arends MJ, et al. Endogenous formaldehyde is a hematopoietic stem cell genotoxin and metabolic carcinogen. Mol Cell. 2015;60:177\u201388.","journal-title":"Mol Cell"},{"key":"2687_CR3","doi-asserted-by":"publisher","first-page":"2119","DOI":"10.1182\/blood.2019004316","volume":"139","author":"M Wang","year":"2022","unstructured":"Wang M, Dingler FA, Patel KJ. Genotoxic aldehydes in the hematopoietic system. Blood. 2022;139:2119\u201329.","journal-title":"Blood"},{"key":"2687_CR4","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1177\/0192623312466459","volume":"41","author":"JA Swenberg","year":"2013","unstructured":"Swenberg JA, Moeller BC, Lu K, Rager JE, Fry RC, Starr TB. Formaldehyde carcinogenicity research: 30 years and counting for mode of action, epidemiology, and cancer risk assessment. Toxicol Pathol. 2013;41:181\u20139.","journal-title":"Toxicol Pathol"},{"key":"2687_CR5","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.cbpa.2012.09.015","volume":"16","author":"LJ Walport","year":"2012","unstructured":"Walport LJ, Hopkinson RJ, Schofield CJ. Mechanisms of human histone and nucleic acid demethylases. Curr Opin Chem Biol. 2012;16:525\u201334.","journal-title":"Curr Opin Chem Biol"},{"key":"2687_CR6","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1038\/nature23904","volume":"548","author":"G Burgos-Barragan","year":"2017","unstructured":"Burgos-Barragan G, Wit N, Meiser J, Dingler FA, Pietzke M, Mulderrig L, et al. Erratum: mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism. Nature. 2017;548:612.","journal-title":"Nature"},{"key":"2687_CR7","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/j.molcel.2020.11.040","volume":"80","author":"X Shen","year":"2020","unstructured":"Shen X, Wang R, Kim MJ, Hu Q, Hsu CC, Yao J, et al. A surge of DNA damage links transcriptional reprogramming and hematopoietic deficit in fanconi anemia. Mol Cell. 2020;80:1013\u201324.e6.","journal-title":"Mol Cell"},{"key":"2687_CR8","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1038\/s41586-021-04133-7","volume":"600","author":"L Mulderrig","year":"2021","unstructured":"Mulderrig L, Garaycoechea JI, Tuong ZK, Millington CL, Dingler FA, Ferdinand JR, et al. Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response. Nature. 2021;600:158\u201363.","journal-title":"Nature"},{"key":"2687_CR9","doi-asserted-by":"publisher","first-page":"2752","DOI":"10.1016\/j.molcel.2021.05.008","volume":"81","author":"D Di Marcantonio","year":"2021","unstructured":"Di Marcantonio D, Martinez E, Kanefsky JS, Huhn JM, Gabbasov R, Gupta A, et al. ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia. Mol Cell. 2021;81:2752\u201364.e6.","journal-title":"Mol Cell"},{"key":"2687_CR10","first-page":"2372","volume":"141","author":"U Vekariya","year":"2023","unstructured":"Vekariya U, Toma M, Nieborowska-Skorska M, Le BV, Caron MC, Kukuyan AM, et al. DNA polymerase \u03b8 protects leukemia cells from metabolically induced DNA damage. Blood. 2023;141:2372\u201389.","journal-title":"Blood"},{"key":"2687_CR11","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1002\/em.20534","volume":"51","author":"L Zhang","year":"2010","unstructured":"Zhang L, Freeman LE, Nakamura J, Hecht SS, Vandenberg JJ, Smith MT, et al. Formaldehyde and leukemia: epidemiology, potential mechanisms, and implications for risk assessment. Environ Mol Mutagen. 2010;51:181\u201391.","journal-title":"Environ Mol Mutagen"},{"key":"2687_CR12","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1007\/s00204-016-1760-5","volume":"91","author":"C Wei","year":"2017","unstructured":"Wei C, Wen H, Yuan L, McHale CM, Li H, Wang K, et al. Formaldehyde induces toxicity in mouse bone marrow and hematopoietic stem\/progenitor cells and enhances benzene-induced adverse effects. Arch Toxicol. 2017;91:921\u201333. Epub 2016 Jun 23.","journal-title":"Arch Toxicol"},{"key":"2687_CR13","doi-asserted-by":"publisher","first-page":"5525","DOI":"10.1021\/bi00565a010","volume":"19","author":"YF Chaw","year":"1980","unstructured":"Chaw YF, Crane LE, Lange P, Shapiro R. Isolation and identification of cross-links from formaldehyde-treated nucleic acids. Biochemistry. 1980;19:5525\u201331.","journal-title":"Biochemistry"},{"key":"2687_CR14","doi-asserted-by":"publisher","first-page":"S130","DOI":"10.1093\/toxsci\/kfq371","volume":"120","author":"JA Swenberg","year":"2011","unstructured":"Swenberg JA, Lu K, Moeller BC, Gao L, Upton PB, Nakamura J, et al. Endogenous versus exogenous DNA adducts: their role in carcinogenesis, epidemiology, and risk assessment. Toxicol Sci. 2011;120:S130\u201345.","journal-title":"Toxicol Sci"},{"key":"2687_CR15","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1021\/tx025614r","volume":"16","author":"G Cheng","year":"2003","unstructured":"Cheng G, Shi Y, Sturla SJ, Jalas JR, McIntee EJ, Villalta PW, et al. Reactions of formaldehyde plus acetaldehyde with deoxyguanosine and DNA: formation of cyclic deoxyguanosine adducts and formaldehyde cross-links. Chem Res Toxicol. 2003;16:145\u201352.","journal-title":"Chem Res Toxicol"},{"key":"2687_CR16","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1093\/toxres\/tfaa079","volume":"9","author":"L Bernardini","year":"2020","unstructured":"Bernardini L, Barbosa E, Char\u00e3o MF, Goethel G, Muller D, Bau C, et al. Oxidative damage, inflammation, genotoxic effect, and global DNA methylation caused by inhalation of formaldehyde and the purpose of melatonin. Toxicol Res Camb. 2020;9:778\u201389.","journal-title":"Toxicol Res Camb"},{"key":"2687_CR17","doi-asserted-by":"publisher","DOI":"10.1186\/s41021-016-0037-9","volume":"38","author":"S Hashimoto","year":"2016","unstructured":"Hashimoto S, Anai H, Hanada K. Mechanisms of interstrand DNA crosslink repair and human disorders. Genes Environ. 2016;38:9.","journal-title":"Genes Environ"},{"key":"2687_CR18","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1016\/j.molcel.2020.10.012","volume":"80","author":"FA Dingler","year":"2020","unstructured":"Dingler FA, Wang M, Mu A, Millington CL, Oberbeck N, Watcham S, et al. Two aldehyde clearance systems are essential to prevent lethal formaldehyde accumulation in mice and humans. Mol Cell. 2020;80:996\u20131012.e9.","journal-title":"Mol Cell"},{"key":"2687_CR19","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1182\/blood.2020009111","volume":"137","author":"A Mu","year":"2021","unstructured":"Mu A, Hira A, Niwa A, Osawa M, Yoshida K, Mori M, et al. Analysis of disease model iPSCs derived from patients with a novel Fanconi anemia-like IBMFS ADH5\/ALDH2 deficiency. Blood. 2021;137:2021\u201332.","journal-title":"Blood"},{"key":"2687_CR20","doi-asserted-by":"publisher","DOI":"10.1186\/s41021-020-00160-4","volume":"42","author":"J Nakamura","year":"2020","unstructured":"Nakamura J, Holley DW, Kawamoto T, Bultman SJ. The failure of two major formaldehyde catabolism enzymes (ADH5 and ALDH2) leads to partial synthetic lethality in C57BL\/6 mice. Genes Environ. 2020;42:21.","journal-title":"Genes Environ"},{"key":"2687_CR21","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s12929-017-0327-y","volume":"24","author":"JS Chang","year":"2017","unstructured":"Chang JS, Hsiao JR, Chen CH. ALDH2 polymorphism and alcohol-related cancers in Asians: a public health perspective. J Biomed Sci. 2017;24:19.","journal-title":"J Biomed Sci"},{"key":"2687_CR22","doi-asserted-by":"crossref","unstructured":"Chen CH, Kraemer BR, Mochly-Rosen D. ALDH2 variance in disease and populations. Dis Model Mech. 2022;15:dmm049601.","DOI":"10.1242\/dmm.049601"},{"key":"2687_CR23","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/ejhg.2011.184","volume":"20","author":"F Takeuchi","year":"2012","unstructured":"Takeuchi F, Yokota M, Yamamoto K, Nakashima E, Katsuya T, Asano H, et al. Genome-wide association study of coronary artery disease in the Japanese. Eur J Hum Genet. 2012;20:333\u201340.","journal-title":"Eur J Hum Genet"},{"key":"2687_CR24","doi-asserted-by":"publisher","first-page":"e50","DOI":"10.1371\/journal.pmed.1000050","volume":"6","author":"PJ Brooks","year":"2009","unstructured":"Brooks PJ, Enoch MA, Goldman D, Li TK, Yokoyama A. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS Med. 2009;6:e50.","journal-title":"PLoS Med"},{"key":"2687_CR25","doi-asserted-by":"crossref","unstructured":"Oka Y, Hamada M, Nakazawa Y, Muramatsu H, Okuno Y, Higasa K, et al. Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome. Sci Adv. 2020;6:eabd7197.","DOI":"10.1126\/sciadv.abd7197"},{"key":"2687_CR26","doi-asserted-by":"publisher","first-page":"11117","DOI":"10.1158\/0008-5472.CAN-07-3028","volume":"67","author":"JR Ridpath","year":"2007","unstructured":"Ridpath JR, Nakamura A, Tano K, Luke AM, Sonoda E, Arakawa H, et al. Cells deficient in the FANC\/BRCA pathway are hypersensitive to plasma levels of formaldehyde. Cancer Res. 2007;67:11117\u201322.","journal-title":"Cancer Res"},{"key":"2687_CR27","doi-asserted-by":"publisher","first-page":"108820","DOI":"10.1016\/j.celrep.2021.108820","volume":"34","author":"G Chandramouly","year":"2021","unstructured":"Chandramouly G, Liao S, Rusanov T, Borisonnik N, Calbert ML, Kent T, et al. Pol\u03b8 promotes the repair of 5\u2019-DNA-protein crosslinks by microhomology-mediated end-joining. Cell Rep. 2021;34:108820.","journal-title":"Cell Rep"},{"key":"2687_CR28","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1016\/j.molcel.2016.06.020","volume":"63","author":"DW Wyatt","year":"2016","unstructured":"Wyatt DW, Feng W, Conlin MP, Yousefzadeh MJ, Roberts SA, Mieczkowski P, et al. Essential roles for polymerase theta-mediated end joining in the repair of chromosome breaks. Mol Cell. 2016;63:662\u201373.","journal-title":"Mol Cell"},{"key":"2687_CR29","doi-asserted-by":"publisher","first-page":"3909","DOI":"10.1074\/jbc.RA118.005188","volume":"294","author":"Z Wang","year":"2019","unstructured":"Wang Z, Song Y, Li S, Kurian S, Xiang R, Chiba T, et al. DNA polymerase \u03b8 (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse. J Biol Chem. 2019;294:3909\u201319.","journal-title":"J Biol Chem"},{"key":"2687_CR30","doi-asserted-by":"publisher","first-page":"111716","DOI":"10.1016\/j.celrep.2022.111716","volume":"41","author":"A Schrempf","year":"2022","unstructured":"Schrempf A, Bernardo S, Arasa Verge EA, Ramirez Otero MA, Wilson J, Kirchhofer D, et al. POL\u03b8 processes ssDNA gaps and promotes replication fork progression in BRCA1-deficient cells. Cell Rep. 2022;41:111716.","journal-title":"Cell Rep"},{"key":"2687_CR31","doi-asserted-by":"publisher","first-page":"4218","DOI":"10.1016\/j.molcel.2022.09.013","volume":"82","author":"A Mann","year":"2022","unstructured":"Mann A, Ramirez-Otero MA, De Antoni A, Hanthi YW, Sannino V, Baldi G, et al. POL\u03b8 prevents MRE11-NBS1-CtIP-dependent fork breakage in the absence of BRCA2\/RAD51 by filling lagging-strand gaps. Mol Cell. 2022;82:4218\u201331.e8.","journal-title":"Mol Cell"},{"key":"2687_CR32","doi-asserted-by":"publisher","first-page":"4664","DOI":"10.1016\/j.molcel.2022.11.008","volume":"82","author":"O Belan","year":"2022","unstructured":"Belan O, Sebald M, Adamowicz M, Anand R, Vancevska A, Neves J, et al. POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells. Molecular cell. 2022;82:4664\u201380.e9.","journal-title":"Molecular cell"},{"key":"2687_CR33","doi-asserted-by":"crossref","unstructured":"Barszczewska-Pietraszek G, Drzewiecka M, Czarny P, Skorski T, \u015aliwi\u0144ski T. Pol\u03b8 inhibition: an anticancer therapy for HR-deficient tumours. Int J Mol Sci. 2022;24:319.","DOI":"10.3390\/ijms24010319"},{"key":"2687_CR34","doi-asserted-by":"publisher","first-page":"3127","DOI":"10.1016\/j.celrep.2018.05.034","volume":"23","author":"K Sullivan-Reed","year":"2018","unstructured":"Sullivan-Reed K, Bolton-Gillespie E, Dasgupta Y, Langer S, Siciliano M, Nieborowska-Skorska M, et al. Simultaneous targeting of PARP1 and RAD52 triggers dual synthetic lethality in BRCA-deficient tumor cells. Cell Rep. 2018;23:3127\u201336.","journal-title":"Cell Rep"},{"key":"2687_CR35","doi-asserted-by":"publisher","first-page":"2392","DOI":"10.1172\/JCI90825","volume":"127","author":"M Nieborowska-Skorska","year":"2017","unstructured":"Nieborowska-Skorska M, Sullivan K, Dasgupta Y, Podszywalow-Bartnicka P, Hoser G, Maifrede S, et al. Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. J Clin Invest. 2017;127:2392\u2013406.","journal-title":"J Clin Invest"},{"key":"2687_CR36","doi-asserted-by":"publisher","first-page":"5089","DOI":"10.1158\/0008-5472.CAN-20-3761","volume":"81","author":"S Maifrede","year":"2021","unstructured":"Maifrede S, Le BV, Nieborowska-Skorska M, Golovine K, Sullivan-Reed K, Dunuwille WMB, et al. TET2 and DNMT3A mutations exert divergent effects on DNA repair and sensitivity of leukemia cells to PARP inhibitors. Cancer Res. 2021;81:5089\u2013101.","journal-title":"Cancer Res"},{"key":"2687_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50158-7","volume":"15","author":"U Vekariya","year":"2024","unstructured":"Vekariya U, Minakhin L, Chandramouly G, Tyagi M, Kent T, Sullivan-Reed K, et al. PARG is essential for Poltheta-mediated DNA end-joining by removing repressive poly-ADP-ribose marks. Nat Commun. 2024;15:5822.","journal-title":"Nat Commun"},{"key":"2687_CR38","doi-asserted-by":"publisher","first-page":"7720","DOI":"10.1073\/pnas.1213431110","volume":"110","author":"LN Truong","year":"2013","unstructured":"Truong LN, Li Y, Shi LZ, Hwang PY, He J, Wang H, et al. Microhomology-mediated end joining and homologous recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells. Proc Natl Acad Sci USA. 2013;110:7720\u20135.","journal-title":"Proc Natl Acad Sci USA"},{"key":"2687_CR39","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.cotox.2018.07.001","volume":"9","author":"H Reingruber","year":"2018","unstructured":"Reingruber H, Pontel LB. Formaldehyde metabolism and its impact on human health. Current Opin Toxicol. 2018;9:28\u201334.","journal-title":"Current Opin Toxicol"},{"key":"2687_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28242-7","volume":"13","author":"C Umansky","year":"2022","unstructured":"Umansky C, Morellato AE, Rieckher M, Scheidegger MA, Martinefski MR, Fern\u00e1ndez GA, et al. Endogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity. Nat Commun. 2022;13:745.","journal-title":"Nat Commun"},{"key":"2687_CR41","doi-asserted-by":"crossref","unstructured":"Lanz J, Biniaz-Harris N, Kuvaldina M, Jain S, Lewis K, Fallon BA. Disulfiram: mechanisms, applications, and challenges. Antibiotics. 2023;12:524.","DOI":"10.3390\/antibiotics12030524"},{"key":"2687_CR42","doi-asserted-by":"publisher","first-page":"2157","DOI":"10.1021\/bi201785u","volume":"51","author":"LS Green","year":"2012","unstructured":"Green LS, Chun LE, Patton AK, Sun X, Rosenthal GJ, Richards JP. Mechanism of inhibition for N6022, a first-in-class drug targeting S-nitrosoglutathione reductase. Biochemistry. 2012;51:2157\u201368.","journal-title":"Biochemistry"},{"key":"2687_CR43","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23463-8","volume":"12","author":"D Zatreanu","year":"2021","unstructured":"Zatreanu D, Robinson HMR, Alkhatib O, Boursier M, Finch H, Geo L, et al. Pol\u03b8 inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat Commun. 2021;12:3636.","journal-title":"Nat Commun"},{"key":"2687_CR44","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1038\/nature14184","volume":"518","author":"R Ceccaldi","year":"2015","unstructured":"Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, et al. Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair. Nature. 2015;518:258\u201362.","journal-title":"Nature"},{"key":"2687_CR45","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1038\/nature14157","volume":"518","author":"PA Mateos-Gomez","year":"2015","unstructured":"Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E, Sfeir A. Mammalian polymerase theta promotes alternative NHEJ and suppresses recombination. Nature. 2015;518:254\u20137.","journal-title":"Nature"},{"key":"2687_CR46","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1158\/1541-7786.MCR-22-1035","volume":"21","author":"K Sullivan-Reed","year":"2023","unstructured":"Sullivan-Reed K, Toma MM, Drzewiecka M, Nieborowska-Skorska M, Nejati R, Karami A, et al. Simultaneous targeting of DNA polymerase theta and PARP1 or RAD52 triggers dual synthetic lethality in homologous recombination-deficient leukemia cells. Mol Cancer Res. 2023;21:1017\u201322.","journal-title":"Mol Cancer Res"},{"key":"2687_CR47","doi-asserted-by":"publisher","first-page":"13198","DOI":"10.1021\/acs.jmedchem.2c00998","volume":"65","author":"M Bubenik","year":"2022","unstructured":"Bubenik M, Mader P, Mochirian P, Vall\u00e9e F, Clark J, Truchon JF, et al. Identification of RP-6685, an orally bioavailable compound that inhibits the DNA polymerase activity of Pol\u03b8. J Med Chem. 2022;65:13198\u2013215.","journal-title":"J Med Chem"},{"key":"2687_CR48","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/nrm.2017.56","volume":"18","author":"J Stingele","year":"2017","unstructured":"Stingele J, Bellelli R, Boulton SJ. Mechanisms of DNA-protein crosslink repair. Nat Rev Mol Cell Biol. 2017;18:563\u201373.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2687_CR49","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.molcel.2016.10.010","volume":"64","author":"RA Deshpande","year":"2016","unstructured":"Deshpande RA, Lee JH, Arora S, Paull TT. Nbs1 converts the human Mre11\/Rad50 nuclease complex into an endo\/exonuclease machine specific for protein-DNA adducts. Mol Cell. 2016;64:593\u2013606.","journal-title":"Mol Cell"},{"key":"2687_CR50","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13610-7","volume":"10","author":"C Bruhn","year":"2019","unstructured":"Bruhn C, Foiani M. A model of DNA damage response activation at stalled replication forks by SPRTN. Nat Commun. 2019;10:5671.","journal-title":"Nat Commun"},{"key":"2687_CR51","doi-asserted-by":"publisher","first-page":"8271","DOI":"10.1093\/nar\/gkae519","volume":"52","author":"M Rieckher","year":"2024","unstructured":"Rieckher M, Gallrein C, Alquezar-Artieda N, Bourached-Silva N, Vaddavalli Pavana L, Mares D, et al. Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging. Nucleic Acids Res. 2024;52:8271\u201385.","journal-title":"Nucleic Acids Res"},{"key":"2687_CR52","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-35802-y","volume":"14","author":"Y Gao","year":"2023","unstructured":"Gao Y, Guitton-Sert L, Dessapt J, Coulombe Y, Rodrigue A, Milano L, et al. A CRISPR-Cas9 screen identifies EXO1 as a formaldehyde resistance gene. Nat Commun. 2023;14:381.","journal-title":"Nat Commun"},{"key":"2687_CR53","doi-asserted-by":"publisher","first-page":"8953","DOI":"10.1093\/nar\/gks670","volume":"40","author":"M Enoiu","year":"2012","unstructured":"Enoiu M, Jiricny J, Sch\u00e4rer OD. Repair of cisplatin-induced DNA interstrand crosslinks by a replication-independent pathway involving transcription-coupled repair and translesion synthesis. Nucleic Acids Res. 2012;40:8953\u201364.","journal-title":"Nucleic Acids Res"},{"key":"2687_CR54","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1038\/s41556-024-01401-2","volume":"26","author":"Y Oka","year":"2024","unstructured":"Oka Y, Nakazawa Y, Shimada M, Ogi T. Endogenous aldehyde-induced DNA-protein crosslinks are resolved by transcription-coupled repair. Nat Cell Biol. 2024;26:784\u201396.","journal-title":"Nat Cell Biol"},{"key":"2687_CR55","doi-asserted-by":"publisher","first-page":"eadg2235","DOI":"10.1126\/sciadv.adg2235","volume":"9","author":"N Wit","year":"2023","unstructured":"Wit N, Gogola E, West JA, Vornb\u00e4umen T, Seear RV, Bailey PSJ, et al. A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production. Sci Adv. 2023;9:eadg2235.","journal-title":"Sci Adv"},{"key":"2687_CR56","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/nature10192","volume":"475","author":"F Langevin","year":"2011","unstructured":"Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ. Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice. Nature. 2011;475:53\u20138.","journal-title":"Nature"},{"key":"2687_CR57","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1038\/nature11368","volume":"489","author":"JI Garaycoechea","year":"2012","unstructured":"Garaycoechea JI, Crossan GP, Langevin F, Daly M, Arends MJ, Patel KJ. Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature. 2012;489:571\u20135.","journal-title":"Nature"},{"key":"2687_CR58","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1089\/ars.2016.6895","volume":"27","author":"M Bodas","year":"2017","unstructured":"Bodas M, Silverberg D, Walworth K, Brucia K, Vij N. Augmentation of S-nitrosoglutathione controls cigarette smoke-induced inflammatory-oxidative stress and chronic obstructive pulmonary disease-emphysema pathogenesis by restoring cystic fibrosis transmembrane conductance regulator function. Antioxid Redox Signal. 2017;27:433\u201351.","journal-title":"Antioxid Redox Signal"},{"key":"2687_CR59","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1002\/iid3.220","volume":"6","author":"LG Que","year":"2018","unstructured":"Que LG, Yang Z, Lugogo NL, Katial RK, Shoemaker SA, Troha JM, et al. Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma. Immun Inflamm Dis. 2018;6:322\u201331.","journal-title":"Immun Inflamm Dis"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02687-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02687-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02687-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T05:37:00Z","timestamp":1757223420000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02687-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,10]]},"references-count":59,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["2687"],"URL":"https:\/\/doi.org\/10.1038\/s41375-025-02687-3","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,10]]},"assertion":[{"value":"20 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 June 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 July 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}