The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential oncogenic activity.

Simian virus 40 (SV40) is a monkey virus associated with several types of human cancers. SV40 is most frequently detected in mesotheliomas, brain and bone tumors and lymphomas, but the mechanism for SV40 tumorigenesis in humans is not clear. SV40 relative Merkel cell polyomavirus (MCPyV) causes Merkel cell carcinoma (MCC) in humans by expressing truncated large tumor antigen (LT) caused by APOBEC cytidine deaminase family enzymes induced mutations. AID (activation-induced cytidine deaminase), a member of the APOBEC family, is the initiator of the antibody diversification process known as somatic hypermutation (SHM) and its aberrant expression and targeting is a frequent source of lymphomagenesis. In this study, we investigated whether AID-induced mutations could cause truncation of SV40 LT. We demonstrate that the SV40 enhancer has strong SHM targeting activity in several cell types and that AID-induced mutations accumulate to SV40 LT in B cells and kidney cells and cause truncated LT expression in B cells. Our results argue that the ability of the SV40 enhancer to target SHM to LT is a potential source of LT truncation events in various cell types that could contribute to carcinogenesis.

RORγt up-regulates RAG gene expression in DP thymocytes to expand the Tcra repertoire.

Recombination activating gene (RAG) expression increases as thymocytes transition from the CD4-CD8- double-negative (DN) to the CD4+CD8+ double-positive (DP) stage, but the physiological importance and mechanism of transcriptional up-regulation are unknown. Here, we show that a DP-specific component of the recombination activating genes antisilencer (DPASE) provokes elevated RAG expression in DP thymocytes. Mouse DP thymocytes lacking the DPASE display RAG expression equivalent to that in DN thymocytes, but this supports only a partial Tcra repertoire due to inefficient secondary Vα-Jα rearrangement. These data indicate that RAG up-regulation is required for a replete Tcra repertoire and that RAG expression is fine-tuned during lymphocyte development to meet the requirements of distinct antigen receptor loci. We further show that transcription factor RORγt directs RAG up-regulation in DP thymocytes by binding to the DPASE and that RORγt influences the Tcra repertoire by binding to the Tcra enhancer. These data, together with prior work showing RORγt to control Tcra rearrangement by regulating DP thymocyte proliferation and survival, reveal RORγt to orchestrate multiple pathways that support formation of the Tcra repertoire.