Fanconi anemia: current insights regarding epidemiology, cancer, and DNA repair

Fanconi anemia is a genetic disorder that is characterized by bone marrow failure, as well as a predisposition to malignancies including leukemia and squamous cell carcinoma (SCC). At least 22 genes are associated with Fanconi anemia, constituting the Fanconi anemia DNA repair pathway. This pathway coordinates multiple processes and proteins to facilitate the repair of DNA adducts including interstrand crosslinks (ICLs) that are generated by environmental carcinogens, chemotherapeutic crosslinkers, and metabolic products of alcohol. ICLs can interfere with DNA transactions, including replication and transcription. If not properly removed and repaired, ICLs cause DNA breaks and lead to genomic instability, a hallmark of cancer. In this review, we will discuss the genetic and phenotypic characteristics of Fanconi anemia, the epidemiology of the disease, and associated cancer risk. The sources of ICLs and the role of ICL-inducing chemotherapeutic agents will also be discussed. Finally, we will review the detailed mechanisms of ICL repair via the Fanconi anemia DNA repair pathway, highlighting critical regulatory processes. Together, the information in this review will underscore important contributions to Fanconi anemia research in the past two decades.

Automated summary

Fanconi anemia is a genetic disorder characterized by bone marrow failure and a predisposition to malignancies. It is associated with at least 22 genes in the Fanconi anemia DNA repair pathway, which is responsible for repairing DNA adducts generated by environmental carcinogens, chemotherapeutic crosslinkers, and alcohol metabolites. If not properly repaired, these adducts can cause DNA breaks and genomic instability, leading to cancer. This review discusses the genetic and phenotypic characteristics of Fanconi anemia, the epidemiology of the disease, and the associated cancer risk. It also explores the sources of DNA adducts and the role of chemotherapy drugs in inducing them. Additionally, the review examines the detailed mechanisms of DNA adduct repair through the Fanconi anemia DNA repair pathway, emphasizing critical regulatory processes.