RNA helicases as regulators of the response of B-cells to programmed DNA rearrangements (360G-Wellcome-220196_Z_20_Z)

In mature B-cells, the generation of antibodies of different isotypes relies on class switch recombination (CSR) mechanisms. Although crucial for adaptive immunity, CSR imposes challenges to genome integrity as it involves programmed induction of DNA double-strand breaks (DSBs) in rapidly proliferating B-cells. A key player in the cellular response to CSR DSBs is the protein kinase ataxia telangiectasia mutated (ATM). Evidence suggests RNA-dependent mechanisms control the DNA damage response by ATM, although there is very limited understanding of how these function in B-cells and which RNA-binding proteins (RBPs) are required for CSR. This proposal aims to define the critical roles of RNA helicases as integrators of ATM signals to control class switch recombination mechanisms in B-cells. I propose an integrative approach combining genomic and proteomic methodologies together with ex vivo B-cell differentiation systems and conditional gene-targeting in mice. I will determine RNA helicase-dependent mechanisms controlling the cell-cycle and CSR DSB-repair and investigate their roles in B-cell immune responses. This work will provide new insight into RNA helicase-mediated pathological mechanisms resulting in CSR deregulation and the development of immune disease or B-cell lymphomagenesis.