The Role of CtIP in Lymphocyte Development and Lymphomagenesis

Chromosomal translocation is a characteristic feature of human lymphoid malignancies and a driver of the initiation and progression of the disease. They arise from the mis-repair of physiological DNA double-strand breaks (DSBs) generated during the assembly and subsequent modifications of the antigen receptor gene loci, namely V(D)J recombination and class switch recombination (CSR). Mammalian cells have three DSB repair pathways –classical non-homologous end-joining (cNHEJ), alternative end-joining (A-EJ), and homologous recombination. DNA end-resection that generates a single-strand 3’ overhang is a critical regulator for the repair pathway choice. Specifically, localized end-resection prevents cNHEJ and exposes flanking microhomology (MH) to promote error-prone A-EJ. In addition to DNA repair, DNA end-resection generates extended single-strand DNA, which activates the ATR-mediated cell cycle checkpoint and indirectly contributes to genomic integrity. The central goal of my thesis research is to investigate the physiological role of DNA end-resection initiation in lymphocyte development and lymphomagenesis. DNA end-resection in mammalian cells is mostly initiated by the endonucle