ALDH9A1 deficiency as a source of endogenous DNA damage that requires repair by the Fanconi anemia pathway
The Fanconi anemia (FA) DNA repair pathway is required for the repair of DNA interstrand cross-links (ICLs). ICLs are caused by genotoxins, such as chemotherapeutic agents or reactive aldehydes. Inappropriately repaired ICLs contribute to hematopoietic stem cell (HSC) failure and tumorigenesis. While endogenous acetaldehyde and formaldehyde are known to induce HSC failure and leukemia in FA patients, the effects of other toxic metabolites on FA pathogenesis have not been systematically investigated. Using a metabolism-focused CRISPR screen, we found a synthetically lethal interaction between ALDH9A1 and the deficiency of the FA pathway. Combined deficiency of ALDH9A1 and FANCD2 causes genomic instability, apoptosis, and decreased hematopoietic colony formation. Fanca-/-Aldh9a1-/- mice exhibited an increased incidence of ovarian tumors. A suppressor CRISPR screen revealed that the loss of ATP13A3, a polyamine transporter, resulted in improved survival of FANCD2-/-ALDH9A1-/- cells. These findings nominate high intracellular polyamines and the resulting 3-aminopropanal and acrolein as sources of endogenous DNA damage in patients with FA.
Authors
- Haruna B. Choijilsuren (ORCID: https://orcid.org/0000-0002-7599-6207)
- Raymond J. Noonan (ORCID: https://orcid.org/0000-0002-7354-8486)
- Sunandini Sridhar (ORCID: https://orcid.org/0000-0002-6991-1860)
- Fan Yang (ORCID: https://orcid.org/0009-0002-2260-5476)
- Danielle Keahi
- Francis P. Lach (ORCID: https://orcid.org/0000-0003-3708-7122)
- Ryan R. White (ORCID: https://orcid.org/0000-0001-8344-2549)
- Jung-Woo Kim (ORCID: https://orcid.org/0000-0001-8877-6556)
- Thomas Carroll (ORCID: https://orcid.org/0000-0002-0073-1714)
- Audrey Goldfarb
- Ileana C. Miranda (ORCID: https://orcid.org/0000-0003-3168-0515)
- Mia D. Stein
- Sangmoo Jeong (ORCID: https://orcid.org/0000-0001-9428-6668)
- Tom Wiley (ORCID: https://orcid.org/0000-0002-4775-6556)
- Moonjung Jung (ORCID: https://orcid.org/0000-0002-1364-1814)
- Jordan A. Durmaz
- Agata Smogorzewska (ORCID: https://orcid.org/0000-0001-6285-1562)
- Isaac Ilyashov
- Habin Bea
- Yeji Park
- Claudia Wong (ORCID: https://orcid.org/0009-0000-8353-1381)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Ewha Womans University (KR)
- Johns Hopkins University (US)
- Cornell University (US)
- Johns Hopkins Medicine (US)
- Cancer Research Center (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
- Rockefeller University (US)
Publication Details
- Journal
- The Journal of Cell Biology
- Published
- 2025-05-03
- DOI
- https://doi.org/10.1083/jcb.202407141
- Citations
- 7
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Howard Hughes Medical Institute
- American Society of Hematology
- Memorial Sloan-Kettering Cancer Center
- Johns Hopkins University
- Maryland Stem Cell Research Fund
- Korea Health Industry Development Institute
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Center for Advancing Translational Sciences