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Fanconi anemia (FA) is a rare hereditary disorder characterized by hypersensitivity to the interstrand crosslinks (ICLs) induced by cisplatin, mitomycin C, or formaldehyde. We found that inhibition of SLFN11, which has been identified as a dominant determinant of responses to various antitumor drugs such as cisplatin, camptothecin, and PARP inhibitors, rescued ICL sensitivity and partially alleviated FA phenotype by stabilizing replication forks. This suggests that SLFN11 intensifies DNA damage sensitivity in FA cells, and could be a novel therapeutic target for the FA phenotype. We also found that human SLFN11 and mouse Slfn8/9 share a functional similarity. In this review, we summarize the interplay between SLFN11 and DNA damage, including functional analysis of SLFN11 and its mouse ortholog.
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Prenatal and neonatal presentations of multiple congenital anomalies are difficult to diagnose and are associated with an increased risk of lethality. The differential diagnosis of antenatal presentations of radial ray malformations includes Fanconi anemia (FA), an inherited bone marrow failure disorder associated with congenital anomalies in around 75% of affected individuals. Although no definitive genotype-phenotype correlations have been demonstrated, a more severe presentation has been proposed in association with biallelic loss of function variants as opposed to hypomorphic missense variants.
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To counteract the damaging effects of DNA interstrand crosslinks (ICLs), cells have evolved various specialized ICL repair pathways. However, how ICL repair impacts genetic integrity remains incompletely understood. Here, we determined the mutagenic consequences of psoralen ICL repair in the animal model C.
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Hum Reprod Open
February 2025
Chair of Human Genetics, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
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Fanconi Anemia (FA) is a heritable syndrome characterized by DNA damage repair deficits, frequent malformations and a significantly elevated risk of bone marrow failure, leukemia, and mucosal head and neck squamous cell carcinomas (HNSCC). Hematopoietic stem cell gene therapy can prevent marrow failure and lower leukemia risk, but mucosal gene therapy to lower HNSCC risk remains untested. Major knowledge gaps include an incomplete understanding of how rapidly gene-corrected cellular lineages could spread through the oral epithelium, and which delivery parameters are critical for ensuring efficient gene correction.
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