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,
* Department of Pediatrics,
Vermont Cancer Center, and
Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405;
Lovelace Respiratory Research Institute, Albuquerque, NM 87108;
¶ Mount Mansfield Union High School, Jericho, VT 05465;
|| Division of Computational Biology, Department of Biostatistics and Bioinformatics, and
# Department of Immunology, Duke University Medical Center, Durham, NC 27710; and
** Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
V(D)J recombinase mediates rearrangements at immune loci and cryptic recombination signal sequences (cRSS), resulting in a variety of genomic rearrangements in normal lymphocytes and leukemic cells from children and adults. The frequency at which these rearrangements occur and their potential pathologic consequences are developmentally dependent. To gain insight into V(D)J recombinase-mediated events during human development, we investigated 265 coding junctions associated with cRSS sites at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in peripheral T cells from 111 children during the late stages of fetal development through early adolescence. We observed a number of specific V(D)J recombinase processing features that were both age and gender dependent. In particular, TdT-mediated nucleotide insertions varied depending on age and gender, including percentage of coding junctions containing N-nucleotide inserts, predominance of GC nucleotides, and presence of inverted repeats (Pr-nucleotides) at processed coding ends. In addition, the extent of exonucleolytic processing of coding ends was inversely related to age. We also observed a coding-partner-dependent difference in exonucleolytic processing and an age-specific difference in the subtypes of V(D)J-mediated events. We investigated these age- and gender-specific differences with recombination signal information content analysis of the cRSS sites in the human HPRT locus to gain insight into the mechanisms mediating these developmentally specific V(D)J recombinase-mediated rearrangements in humans.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was supported by Grant 6042 from the Leukemia and Lymphoma Society of America, Grant HD35309 from the Institute for Child Health and Human Development, National Institutes of Health Grant HD33648-01, Grant 1003312 from the Burroughs Wellcome Fund, and National Cancer Institute Grants CA77737, CA09094013, and CA22435 to the University of Vermont Cancer Center DNA Analysis Facility. L.G.C. is supported by a Career Award at the Scientific Interface from the Burroughs-Wellcome Fund.
2 Address correspondence and reprint requests to Dr. Barry A. Finette, Department of Pediatrics, E203 Given Building, University of Vermont, Burlington, VT 05405. E-mail address: barry.finette{at}uvm.edu
3 Abbreviations used in this paper: RAG, recombinase-activating gene; cRSS, cryptic RSS; HPRT, hypoxanthine-guanine phosphoribosyltransferase; NHEJ, nonhomologous end joining; RIC, recombination signal information content; RSS, recombination signal sequence; TDIF, TdT-interacting factor.
4 The online version of this article contains supplemental material.
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