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Craig H. Bassing, Ph.D.

Expertise

Research Interests:

Elucidation of molecular mechanisms that mediate the cellular response to DNA damage and direct genomic rearrangements in developing lymphocytes.


Key Words:

DNA repair, genomic instability, transformation, V(D)J recombination, lymphocyte development, cancer


Research Details:

DNA double strand breaks (DSBs) are hazardous lesions. Unfortunately, they also are very common. DSBs arise in every S phase through DNA replication errors and can be induced in any cell cycle phase by exogenous factors like ionizing radiation or endogenous factors like reactive oxygen species. When un-repaired or mis-repaired, DSBs result in genomic instability that can lead to cell death or drive malignant transformation. Thus, cells have evolved efficient, specialized, and redundant mechanisms to sense, respond to, and repair DSBs. This DNA damage response (DDR) integrates cell cycle progression and cellular survival to facilitate high-fidelity repair, or trigger apoptosis if the damage is too severe. An early component of the conserved DDR is the biochemical modification of core histones around DSBs. These chromatin modifications create binding sites that nucleate the hierarchal assembly of protein complexes, which may promote accessibility of damaged DNA, stabilize disrupted DNA strands, and/or transduce DDR signals. One aspect of the lab centers on elucidating mechanisms by which chromatin dynamics integrate DSB repair with cellular proliferation and survival to prevent cancer.

Despite their danger, DSBs are a necessary part of DNA biology. For example, the regulated induction and repair of DSBs within antigen receptor loci during V(D)J recombination and class switch recombination (CSR) is essential for development and function of an immune system capable of adapting and responding to a wide variety of pathogens. Such DSBs also activate the DDR, which ensures the error-free repair of these beneficial genomic lesions. The physiological importance of V(D)J recombination and CSR control mechanisms has been demonstrated by the fact that defects in each can lead to immunodeficiency, autoimmunity, and lymphoma; while the immunological relevance of DDR control mechanisms has been illustrated by observations that deficiency of these can lead to immunodeficiency and lymphomas with antigen receptor locus translocations. These findings suggest that the regulatory mechanisms that control antigen receptor gene rearrangements and the general DDR co-evolved to ensure development of an effective adaptive immune system without conferring substantial predisposition to autoimmunity or cancer upon the host organism. Another aspect of research in the lab centers on elucidating mechanisms by which chromatin dynamics regulate the tissue-, developmental stage-, and allele-specific rearrangement of antigen receptor loci.


Lab Personnel:

Katherine Yang-Iott – Research Associate
Bu Yin – CAMB Graduate Student
Marta Rowh - MD/PhD IGG Graduate Student
Brenna Brady - IGG Graduate Student
Angela Fusello - Postdoctoral Fellow

Appointments

Assistant Professor of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine (2005 – present)

Education

Ph.D., Biology, Duke University (1997)

B.A., Biology, The Johns Hopkins University (1992)

Selected Publications

Yang-Iott, K.S., Carpenter, A.C., Rowh, M.A.W, Steinel, N., Brady, B.L., Hochedlinger, K., Jaenisch, R., and Bassing, C.H.. TCRß feedback signals inhibit the coupling of recombinationally accessible Vß14 segments with DJß complexes. J. Immunol.. Vol 184(3) . 2010 February:1369-78.

Savic, V., Yin, B., Maas, N.L., Bredemeyer, A.L., Carpenter, A.C., Helmink, B.A., Yang-Iott, K.S., Sleckman, B.P., and Bassing, C.H.. Formation of dynamic ?-H2AX structures along broken DNA strands is distinctly regulated by ATM and MDC1 and dependent upon H2AX densities in chromatin.. Molec. Cell. Vol 34. 2009:298-310.

Kadariya, Y., Yin, B., Tang, B., Shinton, S.A., Quinivan, E.P., Hua, X., Klein-Szanto, A., Al-Saleem, T.I., Bassing, C.H., Hardy, R.R., and Kruger, W.D.. Mice heterozygous for germline mutations in methylioadenosine phosphorylase (MTAP) die prematurely of T-cell lymphoma. Cancer Research. Vol 69. 2009:5961-5969.

Yin, B. and Bassing, C.H.. V(D)J recombination causes dangerous chromosome liaisons in developing thymocytes. Cell Cycle. Vol 8. 2009:2486-2487.

Carpenter, A.C., Yang-Iott, K.S., Chao, L., Nuskey, B., Whitlow, S., Alt, F.W., and Bassing, C.H.. Assembled DJß complexes influence TCRß chain selection and peripheral Vß repertoire.. J. Immunol.. Vol 182. 2009:5586-5595.

Helmink, B.A., Bredemeyer, A.L., Lee, B.S., Huang, C.Y., Sharma, G.F., Walker, L.M., Bednarski, J., Lee, W.L., Pandita, T.K., Bassing, C.H., and Sleckman, B.P.. MRN complex function in the repair of chromosomal Rag-mediated DNA double strand breaks.. J. Exp. Med.. Vol 206. 2009:669-679.

Savic, V. and Bassing, C.H.. Chipping away at gamma-H2AX foci. Cell Cycle. Vol 8:3285-90. 2009:3285-90.

Yin, B., Savic, V., Yang-Iott, K.S., Helmink, B.A., Bredemeyer, A.L., Sleckman, B.P., and Bassing, C.H.. Histone H2AX stabilizes broken DNA strands to suppress chromosome translocations and breaks during V(D)J recombination.. Journal of Experimental Medicine. Vol In Press. 2009.

Econmopoulou, M., Celeste, A., Orlova, V.V., Langer, H., Choi, E.Y., Ma, M., Vassilopoulos, A., Deng, C., Bassing, C.H., Tosato, G., Boehm, M., Nussenzweig, A., and Chavakis, T.. Histone H2AX is integral to hypoxia-driven neovascularisation. Nat. Med.. Vol 15. 2009:553-558.

Chanoux, R.A., Yin, B., Urtishak, K.A., Bassing, C.H., and Brown, E.J.. ATR and H2AX cooperate in maintaining genomic stability under replication stress.. J. Biol. Chem.. Vol 284. 2009:5994-6003.