David G Schatz

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..We propose that recombination centers coordinate V(D)J recombination by providing discrete sites within which gene segments are captured for recombination...

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..Our study reveals that the Sin1/mTORC2-Akt2 signaling axis is a key regulator of FoxO1 transcriptional activity in B cells...

..These findings reveal important features of the genetic mechanisms that regulate RAG binding and provide a direct confirmation of the accessibility model...

..These data indicate that at least a regulatory relationship exists between B lymphopoiesis, osteoclastogenesis, and osteoblastogenesis...

..We consider these results in light of the recently reported structure of the catalytic region of TdT...

..Our results indicate that cis-acting elements are important for Ig gene diversification, and we propose that targeting specificity is achieved through the combined action of several Ig locus elements that include the promoter...

..These assays provide a means of assessing RAG-mediated transposition in vivo, and our findings provide insight into the potential for the products of RAG-mediated DNA cleavage to cause genome instability...

..These data demonstrate a previously unsuspected connection between B cell and osteoclast development and a key role for Pax5 in the control of osteoclast development...

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..Thus Ebf1-deficient mice appear to be a new model of lipodystrophy. Ebf1 is a rare example of a transcription factor that regulates both the osteoblast and adipocyte lineages similarly...

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..These findings reveal a previously unsuspected function for the NBD in DNA synapsis and have implications for the regulation of DNA binding and cleavage by RAG1 and RAG2...

..In addition, constitutive AID expression from a transgene accelerated division-linked CSR. Thus, we propose that the division-linked increase in AID expression provides an underlying molecular explanation for division-linked CSR...

..RSS-induced conformational changes of StrRAG1 may influence the interaction of RAG1 with RAG2 and synaptic complex formation...

..A major challenge has been to determine how the transposition activity of the RAG proteins is regulated in vivo. Although a variety of mechanisms have been suggested by recent studies, a clear resolution of this issue remains elusive...

..We conclude that the majority of splenic B cells in IL-7Ralpha-deficient mice originate from the bone marrow and not the fetal liver...

..Our results demonstrate that AID acts broadly on the genome, with the ultimate distribution of mutations determined by a balance between high-fidelity and error-prone DNA repair...

..We propose that this unwinding is uniquely sensed during synapsis of an appropriate 12/23 pair of RSSs...

..This indicates that newly integrated DNA has molecular characteristics that render it susceptible to modification by AID, with implications for how targeting and mis-targeting of AID occurs...

..Here, we discuss possible roles of AID, CSR, and somatic hypermutation in generating chromosomal translocations and in tumor progression...

..These findings indicate that SHM and CSR trigger distinct DNA damage responses and identify a novel histone modification pattern for SHM consisting of H2B(Ser14P) in the absence of gammaH2AX...

..This strand asymmetry is eliminated in mice deficient in mismatch repair, indicating that the error-prone mismatch repair machinery preferentially targets top-strand uracils in a way that promotes SHM during the antibody response...

..The finding of transcribed, histone acetylated gene segments that fail to recombine suggests that a Pax5-dependent regulatory mechanism is required in addition to standard constraints of accessibility to control V(H) gene recombination...

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..Moreover, Artemis functions as a genomic caretaker, most notably in prevention of translocations and telomeric fusions. As Artemis deficiency is compatible with human life, Artemis may also suppress genomic instability in humans...

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..In contrast, the outgrowth of translocation-positive cells was dependent on AID, raising the possibility that AID is important in tumor progression, perhaps by virtue of its mutagenic properties...

..quot; The interplay between such binary and multiplicative modes of interactions provides a general model for analyzing protein-DNA interactions in various biological systems...

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..Our findings indicate that B12/23 restriction of V(D)J recombination is cemented at the level of interactions between the RAG proteins and TCRbeta RS sequences...

..These mice provide a unique system for the inducible activation of V(D)J recombination and the development of primary lymphocytes...

..We review and attempt to reconcile the numerous and sometimes conflicting studies on the targeting of SHM to immunoglobulin loci, and highlight areas that hold promise for further investigation...

..Finally, we propose a model for the formation of RAG-DNA complexes that involves anchoring of RAG1 at the recombination signal nonamer and RAG2-dependent surveillance of adjoining DNA for suitable spacer and heptamer sequences...

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..DC-mediated induction of AID and resultant genomic damage may therefore serve as a double-edged sword and be targeted by approaches such as RANKL inhibition already in the clinic...

..These advances suggest novel mechanisms for both the targeting and the mistargeting of V(D)J recombination, and have implications for how these events contribute to genome instability and lymphoid malignancy...

..Our results suggest that the RAG proteins have an architectural function in facilitating proper and efficient V(D)J joining, and a protective function in preventing degradation of broken ends prior to joining...

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..We propose that multiple, dispersed DNA elements collaborate to recruit and activate the mutational machinery at Ig gene variable regions during SHM...

..Parallels between these three reactions are considered in light of recent advances...

..These studies support the potential clinical utility of combining radiation therapy with agents that inhibit DNA double-strand break repair...

..Thus, the induction of IFN-gamma expression by Hlx depends on a permissive epigenetic state of the IFN-gamma gene locus and/or the molecular context of the immature Th cells...

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