Understanding the Mechanism of Noncanonical Functions of RAGs in Lymphoid Cancer and Glioblastoma

Abstract

Recombination activating genes (RAGs) composed of RAG1 and RAG2, are the endonuclease involved in V(D)J recombination, which is critical for adaptive immunity in mammals. Activation-induced cytidine deaminase (AID), expressed in germinal B cells, deaminates CpG/ methylated CpG, generating single nucleotide mismatch of either U/G or T/G. Several studies suggest that RAGs and AID are the key players responsible for the generation of chromosomal translocations. In summary, noncanonical functions of RAGs were explored in the present study. In the first part, we investigated whether a combination of RAG and AID activities can explain mechanism of uncharacterized fragile regions associated with several lymphoid cancers. Through combination of in silico and biochemical assays, we propose a novel mechanism of generation of chromosomal rearrangements in lymphoid cancers, mediated by both AID and RAGs, where RAGs bind to nonamer and cleave at adjacent mismatch generated due to deamination of meCpG or unmethylated cytosines. In the second part of the thesis, the expression and functional relevance of RAGs in glioblastoma was explored. The present study showed RAGs expression in majority of human glioblastoma cell lines. We show that RAG contributes to recombination events involved in chromosomal aberrations seen in high grade glioma. Our data suggests the potential role of RAGs in chromosomal rearrangements associated with glioblastoma.