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The Role of Chromatin Modifications in DNA Repair, Maintenance of Genomic Stability, and Suppression of Cancer. Human cancer is often associated with chromosomal translocations that arise through errors in the repair of DNA double strand breaks (DSBs). DSBs are among the most hazardous cellular lesions and among the most difficult to repair; however, they also are very common. Consequently, eukaryotic cells have evolved highly efficient, specialized, and redundant molecular mechanisms to sense, respond to, and repair these dangerous lesions. Upon the induction of DSBs, H2AX, a core histone variant, is rapidly phosphorylated (to form ?-H2AX) across large regions of chromatin on both sides of the lesion. We have demonstrated that this biochemical modification of H2AX is essential for a normal cellular response to DSBs. In this conext, we found that H2AX deficiency or haploinsufficiency predisposes cells to accumulation of genomic instability and mice to lymphomas, sarcomas, and other solid tumors, all of which harbor clonal translocations that arise through the mis-repair of spontaneous and/or genetically programmed DSBs. A major research focus of the laboratory is to elucidate the precise molecular mechanisms by which ?-H2AX, other chromatin modifications, and chromatin-associated proteins direct error-free DSB repair, maintain genomic stability, and suppress malignant transformation. Since H2AX maps to a cytogenetic region (11q23) frequently deleted in human cancers and many of the proteins that phosphorylate H2AX or bind ?-H2AX are known human tumor suppressors, our work is likely to have many implications for the understanding, diagnosis, and treatment of human malignancies.
Genetic and Epigenetic Regulation of Antigen Receptor Diversification. The generation of lymphocytes that express a vast repertoire of antigen receptors is essential for an adaptive immune system. Such diversity is achieved through the programmed rearrangement and assembly of antigen receptor genes from component variable (V), diversity (D), and joining (J) gene segments. This process of V(D)J recombination is regulated within the contexts of lineage-specificity, developmental stage-specificity, and allelic-specificity, at least in part through modulation of accessibility of participating V, D, and J gene segments to the lymphocyte-specific RAG endonuclease. Despite intense efforts, much remains to be learned about the molecular mechanisms that determine RAG accessibility and the factors that influence the choice of particular gene segments for recombination. A second major research focus of the laboratory is to elucidate the precise genetic and epigenetic mechanisms that direct the regulated assembly of TCRß gene segments. We have recently found that the productive coupling of RAG accessible Vß segments and DJß complexes is the rate-limiting and regulated step in the assembly of TCRß genes. Our current focus is to elucidate mechanisms by which particular cis -acting DNA elements and trans -acting proteins cooperate to promote Vß RAG accessibility, direct Vß rearrangements across large chromosomal distances, and inhibit secondary Vß rearrangements; all within the contexts of the cellular DSB response. Besides fundamental relevance to biology, elucidation of V(D)J recombination control mechanisms has substantial implications for human health and disease as defects in these underlie many immunological diseases and also can lead to the transformation of lymphocytes via chromosomal translocations that unleash oncogenic activities.
Background
Craig Bassing obtained his Ph.D. from the Duke University Medical School in 1997 where he trained with Xiao-Fan Wang in elucidating molecular mechanisms through which TGF- b signals growth inhibition. Subsequently, Dr. Bassing trained as a Postdoctoral Fellow and then Instructor in the laboratory of Dr. Frederick W. Alt at Harvard Medical School . His work focused on elucidation of the molecular mechanisms that regulate the initiation and proper repair of DNA double strand breaks during chromosomal V(D)J recombination. Dr. Bassing was promoted to an Assistant Professor of Pediatrics at Harvard Medical School in 2004 with his own laboratory as a Junior Investigator of the CBR Institute for Biomedical Research. In January 2005, he joined the faculty of the University of Pennsylvania School of Medicine and the Children's Hospital of Philadelphia as an Assistant Professor in the Department of Laboratory Medicine and Pathology. Dr. Bassing also is an Assistant Professor in the Department of Cancer Biology, an Assistant Investigator of the Abramson Family Cancer Research Institute, and an Investigator of the Joseph Stokes Jr. Research Institute of the Children's Hospital of Philadelphia where his lab is located. |
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