The Jackson Laboratory

Nonhomologous end joining (NHEJ) is a critical DNA repair pathway, with proposed tumor suppression functions in many tissues. Mutations in the NHEJ factors cause severe combined immunodeficiencies in humans and probably increase susceptibility to lymphoma in some cases. We have had a long-term focus on understanding the connections between NHEJ, normal lymphocyte development, and cancer-related genomic instability. Using NHEJ-deficient mice as a starting point, we have developed and studied several different mouse models of specific human lymphomas and leukemias. These mice were used to uncover a new type of cancer-related chromosome aberration, the complicon, and to illuminate the mechanisms by which it forms in lymphoma cells. More recently, we have identified genetic and genomic determinants for complex chromosomal instability, of the type seen in many of the most aggressive cancers. We've discovered that not only the accumulation of specific mutations, but the temporal sequence of their occurrence in tumor cells, can influence the end-stage cancer phenotype. Chromosome abnormalities,  aberrant numbers of chromosomes, rearrangements between different chromosomes, and breakage or fragmentation of chromosomes  are a defining feature of many cancers. We have used our NHEJ-defective mouse tumor models to begin defining genome sequence elements that can influence the pattern of chromosome abnormalities in cancer cells. Finally, we have an active collaboration with Dr. Joel Graber's lab to probe the possible links between DNA damage, repair mechanisms, and mRNA regulation. We have recently uncovered an interesting new avenue of genetic deregulation in cancer, suggesting that excessive or unrepaired DNA breaks can elicit a systematic alteration in mRNA processing. This work may have important implications for understanding early cancer cell origins; for predicting responsivenss or resistance to certain chemotherapies; and for new diagnostic or prognostic assays based on mRNA processing behaviors.