Genetics of Radiation Sensitivity

Ionizing radiation is significantly toxic to cells as well as being a potent mutagen and carcinogen.  Humans and other mammals display considerable population variation in their response to the lethal effects of ionizing radiation.  Historically, there has been much interest in elucidating the genetic bases for this variation both because of the insights to be gained into the cellular pathways controlling DNA damage responses and because of the potential to utilize this information to “personalize” radiation therapy to the specific sensitivities of individual patients.  Sensitivity to DNA damaging agents is particularly amenable to genetic studies because the phenotype can be measured, studied, and complemented in cells ex vivo.  That variation in sensitivity to IR is, in part, controlled by genetic risk factors, is well established; strain specific differences in survival after IR exposure have been observed in multiple species and, in humans, a number of autosomal recessive disorders have been described that are characterized by cellular hypersensitivity to IR.  Despite the relative rarity of patients with these disorders, identification of the underlying genetic lesions has provided key insights into components of the cellular response to IR damage.

For more than 20 years, we have studied the genetics of radiosensitivity in humans, focusing on known recessive genetic disorders that result in the most extreme IR hypersensitivity phenotypes.  These studies have included the localization and fine mapping of ATM, the gene mutated in Ataxia-telangiectasia (A-T), the mapping and cloning of the NBN gene mutated in Nijmegen breakage syndrome (NBS), and the description of Ligase IV Syndrome, in which patients display clinical features similar to NBS but have biallelic inactivating mutations in the LIG4 gene.  In addition to these genetic studies, we also study the function of the cellular pathways in which the products of these genes act, primarily using in vitro mutagenesis approaches and expression in cell lines derived from patients.