Nature<\/a>, also point to an existing drug to inhibit this pathway as a promising strategy to break through chemotherapy resistance.<\/p>\n\u00a0<\/p>\n
The study centers on alpha-ketoglutarate (\u03b1KG), a metabolite which accumulates in DNA repair proficient ovarian tumors. The team first confirmed that \u03b1KG was, in fact, playing a key role in the ability of ovarian cancer cells\u2019 to repair DNA and survive chemotherapy treatment. To understand how this occurred, Aird\u2019s team used a sophisticated CRISPR-based technique to systematically search for the enzyme that enables \u03b1KG to repair DNA, thereby protecting cancer cells from chemotherapy. For nearly 2 decades, researchers studying \u03b1KG in multiple scientific fields focused on its role in driving demethylation, the removal of chemical tags called methyl groups from proteins and other molecules. However, Aird\u2019s group instead identified the enzyme TMLHE, which initiates the body\u2019s own synthesis of carnitine (a molecule most often associated with energy metabolism).<\/p>\n
\u00a0<\/p>\n
\u201cEveryone in the field would have told us to look at the demethylases,\u201d Aird said. \u201cThat\u2019s what the literature pointed to. Finding TMLHE was the moment I thought, \u2018Okay, this is going to be something bigger than what we expected.\u2019\u201d<\/p>\n
\u00a0<\/p>\n
Working closely with Nathaniel Snyder, Ph.D., associate professor in the Aging + Cardiovascular Discovery Center at Lewis Katz School of Medicine at Temple University, and his laboratory, the collaborative team discovered what was a previously unknown metabolic pathway. Elevated \u03b1KG activates TMLHE, which drives carnitine production. Carnitine in turn acts as a molecular \u201cshuttle,\u201d ferrying acetyl groups out of mitochondria and into the cell nucleus, where they are deposited onto histones and act to loosen the DNA-histone complex. Once the DNA-histone complex is loosened, the repair machinery of the cell is able to access and fix damaged chains of DNA.<\/p>\n
\u00a0<\/p>\n
Importantly, when TMLHE or carnitine synthesis is blocked, histone acetylation does not occur at key sites, and the cancer cells\u2019 DNA repair machinery cannot assemble. In turn, the cells become significantly more sensitive to DNA-damaging chemotherapy.<\/p>\n
\u00a0<\/p>\n
\u201cThe connection between \u03b1KG and methylation is well established\u2014that\u2019s what everyone studies,\u201d said Snyder, co-senior author on the paper. \u201cWhat we found is that \u03b1KG is also controlling acetylation through a completely separate route, and that route turns out to be essential for DNA repair. That\u2019s a new piece of biology that nobody had described before.\u201d<\/p>\n
\u00a0<\/p>\n
To advance these findings toward clinical application, the team tested mildronate, a carnitine synthesis inhibitor with a known safety profile in humans. They found that administering mildronate with cisplatin (a platinum-based DNA-damaging chemotherapy drug) reduced tumor burden in mouse models of ovarian cancer, while neither drug alone produced a significant effect.<\/p>\n
\u00a0<\/p>\n
The researchers also found that patients with high TMLHE expression in tumor tissue had significantly worse progression-free survival after chemotherapy, and that elevated serum acetylcarnitine levels at diagnosis correlated independently with faster disease progression. The latter finding raises the possibility that a routine blood test for circulating acetylcarnitine could one day identify patients most likely to resist standard platinum-based cancer treatment and to benefit from combination therapy targeting this newly identified pathway.<\/p>\n
\u00a0<\/p>\n
The implications of the study extend well beyond ovarian cancer. In addition to its involvement across many tumor types, \u03b1KG also declines with age and plays important roles in stem cell biology. Because this study demonstrates for the first time that \u03b1KG influences histone acetylation\u2014and through it, cells\u2019 capacity for DNA repair\u2014scientists have a new way to look at the gene regulation and genomic stability pathways that affect conditions as varied as aging, developmental biology, and a variety of forms of cancer.<\/p>\n
\u00a0<\/p>\n
This discovery was the product of an extensive multi-institutional collaboration spanning metabolomics, biochemistry, and clinical research. Specialized mass spectrometry capabilities from the laboratory of co-corresponding author Snyder were one of many essential contributions to mapping the metabolic pathway in both cell lines and patient samples.<\/p>\n
\u00a0<\/p>\n
\u201cThis paper required so many different people\u2019s energy and expertise,\u201d said Apoorva Uboveja, Ph.D., first author and staff scientist in the Aird lab. \u201cIt\u2019s more fun and more productive to do science in a community. Wistar recognizes and encourages this, and I think the rigor interdisciplinary scope of our work reflects it.\u201d<\/p>\n
\u00a0<\/p>\n
Co-authors: Apoorva Uboveja, Baixue Yang, Raquel Buj, Amandine Amalric, Aidan R. Cole, and Miho Naruse, The Wistar Institute; Julie A. Disharoon and David T. Long, Medical University of South Carolina; Hui Wang, Naveen Kumar Tangudu, Richard S. Fang, Evan Levasseur, Zhentai Huang, Frank P. Vendetti, Jeff Danielson, Esther Elishaev, Kristine Cooper, Nadine Hempel, Wayne Stallaert, and Christopher J. Bakkenist, University of Pittsburgh School of Medicine; Emily Megill, Daniel S. Kantner, Adam Chatoff, Hafsah Ahmad, Mariola M. Marcinkiewicz, Jennifer L. Pennise, Alison Jaccard, Andrea Andress Huacachino, and Nathaniel W. Snyder, Lewis Katz School of Medicine at Temple University; Sarah Graff, Ellen De Pieri, and Simone Sidoli, Albert Einstein College of Medicine; Erika S. Dahl, Penn State College of Medicine; Lauren Borho and Francesmary Modugno, Magee-Womens Research Institute, University of Pittsburgh School of Medicine; Miriam D. Post and Benjamin G. Bitler, University of Colorado Anschutz Medical Campus; and Kathryn E. Wellen, University of Pennsylvania.<\/p>\n
Work supported by: National Institutes of Health (NIH) grants R37CA240625, R01CA259111, R01CA298386, T32GM133332, R01CA242021, R35GM119512, R21CA267050, S10OD030286, T32HL091804, T32GM142606, and P30CA047904; Cancer Center Support Grants P30CA010815 and P30CA047904; P50CA272218 CEP award; the Sandy Rollman Ovarian Cancer Foundation; the American Cancer Society grant RSG-19-113-01-CCG; the Ovarian Cancer Research Alliance grant MIG-2023-2-1018; Congressionally Directed Medical Research Program grants HT9425-23-1-0436 and W81XWH2110338 to FM; HERA Ovarian Cancer Foundation grant; the Melanoma Research Foundation; the Janet Burroughs Ovarian Cancer Foundation; the Hollings Cancer Center Abney Graduate Fellowship; Hevolution Foundation (AFAR); Einstein-Mount Sinai Diabetes Center; the UPMC Hillman Cancer Center; and The Wistar Institute.<\/p>\n
Publication information:\u00a0\u03b1KG-mediated carnitine synthesis drives DNA repair via histone acetylation<\/a>, Nature, 2026. Online publication.<\/p>\n","protected":false},"excerpt":{"rendered":"PHILADELPHIA \u2014 (May 27, 2026) \u2014 Many cancers can be treated by administering DNA-damaging agents, such as platinum-based…\n","protected":false},"author":2,"featured_media":469767,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6],"tags":[61,60,1378,202938,80,184329],"class_list":["post-469766","post","type-post","status-publish","format-standard","has-post-thumbnail","category-technology","tag-ie","tag-ireland","tag-newswise","tag-ovarian-cancerdna-damaging","tag-technology","tag-wistar-institute"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/469766","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/comments?post=469766"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/469766\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media\/469767"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media?parent=469766"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/categories?post=469766"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/tags?post=469766"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}