title: The DNA damage- and transcription-associated protein paxip1 controls thymocyte development and emigration.
abstract: 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 Jα H3K4me3 and germline transcription, suppressed double strand break formation at 3' Jα segments, but resulted in accumulation of unresolved T cell receptor α-chain gene (Tcra) breaks. Moreover, PAXIP1 was essential for release of mature single positive (SP) αβ 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.
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda MD 20892 USA.
authors.forename: Elsa
authors.initials: E
authors.lastname: Callen
authors.forename: Robert B
authors.initials: RB
authors.lastname: Faryabi
authors.forename: Megan
authors.initials: M
authors.lastname: Luckey
authors.forename: Bingtao
authors.initials: B
authors.lastname: Hao
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Daniel
authors.forename: Wenjing
authors.initials: W
authors.lastname: Yang
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Sun
authors.forename: Greg
authors.initials: G
authors.lastname: Dressler
authors.forename: Weiqun
authors.initials: W
authors.lastname: Peng
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
authors.forename: Michael S
authors.initials: MS
authors.lastname: Krangel
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D004249:DNA Damage; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D051379:Mice; D055611:Natural Killer T-Cells / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D049349:Receptors, Lysosphingolipid / Q000235:genetics; D011995:Recombination, Genetic; D000081025:Sphingosine-1-Phosphate Receptors; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; C412792:Paxip1 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors