These findings open the door to establishing new tumor-targeted treatment strategies involving induction of DNA lesions, specifically during chemo- and radiotherapy.
Published December 1 in The Journal of Immunology, the study found that two DNA repair pathways believed to compete during the DNA recombination process — classical non-homologous end-joining and a C-terminal binding protein interacting protein (CtIP)-dependent, alternative end-joining pathway — are simultaneously active during class-switch recombination (CSR), and, rather than competing, they more ably repair different types of double-strand breaks.
The study, “Alternative End-Joining and Classical Nonhomologous End-Joining Pathways Repair Different Types of Double-Strand Breaks during Class-Switch Recombination,” sheds light on how B-cells control antibody CSR, an essential mechanism for the diversification of humoral immune response and the elimination of pathogens, such as viruses and bacteria, from our bodies.
“CSR is a programmed intra-chromosomal recombination event between DNA breaks in B-cells that needs to be tightly regulated to avoid potentially tumor-causing DNA recombination,” explained Verdun, who is senior author of the study and a member of the Sylvester Comprehensive Cancer Center and the Geriatric Research, Education and Clinical Center (GRECC) at the Miami VA Healthcare System.
The study results improve the current working model in the field by putting forth the concept that the structure exposed at the end of DNA breaks plays an important role in determining which pathway will be used for the repair process.
“Our results suggest that by inducing DNA breaks that favor the activity of a specific DNA repair mechanism, tumor cells will be forced to depend on a pathway that we can pharmacologically target,” said Verdun. “These efforts could lead to the development of more efficient treatments that combine pharmacological interventions with ionizing radiation.”
Other Miller School co-authors of the study include Elena M. Cortizas, M.S., research associate of medicine, and Maurice E. Hajjar, who is now a medical student at Brown University. The study also was co-authored by colleagues at the Dr. Javier M. Di Noia laboratory at the Institut de Recherches Cliniques de Montréal and the University of Montréal.
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