Disruption of the Human SCL Locus by "Illegitimate" V-(D)-J Recombinase Activity

Aplan, Peter D.; Lombardi, Donald P.; Ginsberg, Ann M.; Cossman, Jeffrey; Bertness, Virginia; Kirsch, Ilan R.

doi:10.1126/science.2255914

Cited by 269 publications

(167 citation statements)

References 34 publications

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“…Such a mechanism has been implicated in the translocation of the TAL-1 gene that is associated with T-ALL. 33,34 Mutations of p16 gene were not found in our present series. In our previous study and those of others, p16 gene mutation is less frequent than deletion in leukemias.…”

Section: Discussioncontrasting

confidence: 65%

Alterations of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features

et al. 1997

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p16 and p15 genes are putative tumor suppressor genes located on chromosome 9p21. In acute leukemias, alterations of p16 and p15 genes have been reported to occur exclusively in lymphoid lineage. We analyzed alterations of p16 and p15 genes in 46 acute leukemias with MLL gene rearrangements by Southern blot analysis, and investigated the association with clinical characteristics. We identified homozygous deletion of p16 and p15 genes in five (19%) of 27 acute lymphoblastic leukemias (ALLs) and in two (11%) of 19 acute myeloid leukemias (AMLs). Patients with homozygous deletion of p16 and p15 genes showed higher average leukocyte counts (343 × 10 9 /l vs 271 × 10 9 /l) and lower estimated 2-year survival rates than those with normal p16 and p15 genes (14.3 vs 30.7%), although the differences were not statistically significant. In addition, we investigated mutation of p16 gene by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) in 31 patients, but no mutation was found in the patients tested. Our results suggest that alterations of p16 and p15 genes are involved in a subset of acute leukemias with MLL gene rearrangement not only of lymphoid but also of myeloid phenotype. Homozygous deletion of p16 and p15 genes may be a possible adverse prognostic factor, although further analysis would be needed to confirm it.

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Section: Discussioncontrasting

confidence: 65%

Alterations of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features

et al. 1997

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“…Thus, the in vitro cleavage assay appears to more accurately predict functionality of a cRSS than the in silico approach. This conclusion is underscored by the comparison of RIC 23 scores obtained for SIL and SCL. By the RIC 23 score, SCL more closely resembles a functional 23-RSS than SIL, but in cell culture (14) and in in vitro cleavage assays (Fig.…”

Section: Discussionmentioning

confidence: 91%

“…However, since even authentic RSSs exhibit some degree of sequence variability in the heptamer and nonamer, and since mutations in the heptamer, nonamer, and spacer motifs have position-dependent and possibly synergistic effects on recombination efficiency (11), determining whether a given cRSS can support V(D)J recombination is problematic in the absence of functional testing. Therefore, several laboratories have applied a well established extrachromosomal V(D)J recombination assay to assess the functionality of various cRSSs in cell culture (12)(13)(14), including those suspected of mediating chromosomal translocations involving LMO2 (t(11;14)(p13; q11)) (15,16), TAL1 (t(1;14)(p34;q11)) (17), Ttg-1 (t(11; 14)(p15;q11) (18,19), and Hox11 (t(10;14)(q24;q11) (20,21) as well as interstitial deletions involving SIL/SCL (1p32) (22,23) and MTAP/p14 -16 (9p21) (13,24). Perhaps not surprisingly, the putative cRSSs studied to date exhibit a spectrum of activities in these assays, supporting V(D)J recombination at levels from ϳ30-fold to over 20,000-fold less than a consensus RSS.…”

mentioning

confidence: 99%

V(D)J Recombinase Binding and Cleavage of Cryptic Recombination Signal Sequences Identified from Lymphoid Malignancies

Zhang

Swanson

2008

Journal of Biological Chemistry

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To understand the molecular basis for these large differences, we investigated the binding and cleavage of these cRSSs by the RAG1/2 proteins that initiate V(D)J recombination. We find that the RAG proteins comparably bind all cRSSs tested, albeit more poorly than a consensus RSS. We show that four cRSSs that support levels of V(D)J recombination above background levels in cell culture (LMO2, TAL1, Ttg-1, and SIL) are also cleaved by the RAG proteins in vitro with efficiencies ranging from 18 to 70% of a consensus RSS. Cleavage of LMO2 and Ttg-1 by the RAG proteins can also be detected in cell culture using ligation-mediated PCR. In contrast, Hox11 and SCL are nicked but not cleaved efficiently in vitro, and cleavage at other adventitious sites in plasmid substrates may also limit the ability to detect recombination activity at these cRSSs in cell culture.The antigen binding domains of immunoglobulins and T cell receptors are encoded in germ line arrays of V, D, and J gene segments that are assembled into functional variable exons by V(D)J recombination during lymphocyte development (1). The site of recombination is directed by a recombination signal sequence (RSS) 2 that flanks each receptor gene segment and consists of a conserved heptamer (consensus 5Ј-CACAGTG-3Ј) and nonamer (consensus 5Ј-ACAAAAACC-3Ј) separated by either 12 or 23 Ϯ 1 nucleotides of more highly varied sequence. V(D)J recombination can be conceptually divided into two phases, a cleavage phase and a joining phase (2). In the cleavage phase, the lymphoid cell-specific RAG1 and RAG2 (recombination activating gene-1 and -2, respectively) proteins assemble a multiprotein synaptic complex with two RSSs (generally one 12-RSS and one 23-RSS) and introduce a DNA double strand break at each RSS between the heptamer and adjacent coding segment via a nick-hairpin mechanism to yield a blunt 5Ј-phosphorylated signal end and a coding end terminating in a covalently sealed DNA hairpin structure. In the joining phase, the signal ends are generally joined precisely to form signal joints, and the coding ends are processed and joined to form coding joints that typically contain nucleotide additions or deletions at the junction. These processes are normally mediated by components of the nonhomologous end-joining DNA repair pathway.

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“…Interstitial deletions that fuse TAL1 coding sequences to the promoter of an upstream gene, SIL (for SCL interrupting locus), were found subsequently to occur with greater frequency than translocations (Aplan et al, 1990;Bernard et al, 1990;Brown et al, 1990). In still other patients, the gene may be activated in the apparent absence of chromosomal rearrangement .…”

Section: Introductionmentioning

confidence: 99%

p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein

et al. 1999

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Disruption of the Human SCL Locus by "Illegitimate" V-(D)-J Recombinase Activity

Cited by 269 publications

References 34 publications

Alterations of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features

Alterations of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features

V(D)J Recombinase Binding and Cleavage of Cryptic Recombination Signal Sequences Identified from Lymphoid Malignancies

p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein

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