The DNA Damage- and Transcription-Associated Protein Paxip1 Controls Thymocyte Development and Emigration

Histone 3 lysine 4 trimethylation (H3K4me3) is associated with promoters of active genes and found at hot spots for DNA recombination. Here we have shown that PAXIP1 (also known as PTIP), a protein associated with MLL3 and MLL4 methyltransferase and the DNA damage response, regulates RAG-mediated cleavage and repair during V(D)J recombination in CD4(+) CD8(+) DP thymocytes. Loss of PAXIP1 in developing thymocytes diminished J alpha H3K4me3 and germline transcription, suppressed double strand break formation at 3' J alpha segments, but resulted in accumulation of unresolved T cell receptor alpha-chain gene (Tcra) breaks. Moreover, PAXIP1 was essential for release of mature single positive (SP) alpha beta T cells from the thymus through transcriptional activation of sphingosine-1-phosphate receptor S1pr1 as well as for natural killer T cell development. Thus, in addition to maintaining genome integrity during Tcra rearrangements, PAXIP1 controls distinct transcriptional programs during DP differentiation necessary for Tcra locus accessibility, licensing mature thymocytes for trafficking and natural killer T cell development.