All living cells form formaldehyde and acetaldehyde through normal metabolism (also from food and alcohol consumption). However, these aldehydes also induce severe DNA damage, which must be tolerated or repaired to prevent diseases. Currently, ~1 billion people in the world have difficulty in detoxifying aldehydes. Various studies have shown that bone marrow failure (BMF) and leukemia are prominent diseases of Fanconi anemia (FA) patients, due to reduced tolerance and repair of aldehyde-induced DNA damage. Nonetheless, the specific types of DNA damage [DNA base damage and DNA-protein crosslinks (DPCs)] that counteracted by the FA DNA repair pathway are poorly understood. Lack of such knowledge is a critical problem that limits our understanding of the mechanism of BMF and leukemia caused by DNA damage, and compromises our ability to effectively prevent and treat such diseases. The short-term goal of this project is to identify and promote our understanding of the specific type(s) of aldehyde-induced DNA damage that the intact FA DNA repair pathways can repair. Although challenging, we have developed unique ultra-sensitive quantitative assays (unavailable elsewhere) for measuring specific types of DNA damage induced by aldehydes. Other methods available are unable to distinguish specific DNA damage products. Based on our strong preliminary data, we hypothesize that DPCs will be repaired under the intact FA DNA repair pathways. Our long-term goal is to find out which specific aldehyde is most toxic and how DNA damage can be prevented, repaired, and cured. The results of our study will define the nature of DNA damage and lead to the identification of novel therapies and new drugs for managing BMF and leukemia. The work performed here may lead to identification of drugs to help prevent cancer and bone marrow failure in individuals that have mutations in aldehyde processing genes (greater than 1 billion in the world).