The objectives of this proposal are to determine the roles for homologous recombination in genome stability, tumor suppression, and normal development. Chromosomal instability is a major hallmark of many cancers, and chromosome aberrations can be important prognostic markers, with greater instability usually corresponding to poorer outlook. Unfortunately, the underlying molecular mechanisms that prevent or promote chromosomal instability remain largely unknown. Growing evidence implicates unrepaired DNA double strand breaks (DSB) in genome instability. Homologous recombination (HR) represents one critical DSB repair pathway that may be especially important as cells are multiplying. Our central hypothesis is that homologous recombination is crucial for preventing cancer-related genome instability in rapidly dividing cells. We will test this hypothesis by focusing on the function of one important HR pathway component, XRCC2, in lymphocytes. Using a lymphocyte culture system amenable to both in vitro and in vivo studies, we recently showed that XRCC2 is required for normal B-cell development. We will employ this same system to now carry out the specific aims of: 1) Testing the extent to which XRCC2 prevents replication-associated genome instability and tumorigenesis. Using both in vitro and in vivo approaches, we will test Xrcc2-defective cells for spontaneous or induced chromosomal abnormalities, and measure the effects of Xrcc2-deficiency on tumor suppression. 2) Defining the mechanisms of interaction between XRCC2 and the p53 protein. Our data indicate a genetic interaction between Xrcc2 and the gene encoding p53 (Trp53). We will use multiple approaches to test whether this involves direct or indirect physical interaction of the proteins. 3) Measuring the functions of XRCC2 in normal lymphocyte development. Our data suggest that XRCC2 has critical functions, not just in preventing genome instability, but also in promoting normal lymphoid development. To better understand the mechanisms of tumor suppression, we will precisely define the normal lymphoid developmental roles of XRCC2, using in vitro and in vivo approaches. This work will be essential to understanding the molecular origins of chromosomal abnormalities and how they may function to drive cancer development.

Public Health Relevance

Chromosome aberrations are a hallmark of human cancer, and can be useful indicators of patient prognosis. In this proposal we will investigate the origins of cancer-related chromosome aberrations and the mechanisms by which they occur. Identifying these mechanisms will be key to designing better cancer diagnostic tests;refining prognostic markers;and developing new cancer therapies based on tumor-specific properties.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Genetics Study Section (CG)
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Howcroft, Thomas K
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Jackson Laboratory
Bar Harbor
United States
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Ratiu, Jeremy J; Racine, Jeremy J; Hasham, Muneer G et al. (2017) Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes. J Immunol 198:4255-4267
Vuong, Bao Q; Herrick-Reynolds, Kayleigh; Vaidyanathan, Bharat et al. (2013) A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination. Nat Immunol 14:1183-1189
Hasham, Muneer G; Snow, Kathy J; Donghia, Nina M et al. (2012) Activation-induced cytidine deaminase-initiated off-target DNA breaks are detected and resolved during S phase. J Immunol 189:2374-82
Hasham, Muneer G; Donghia, Nina M; Coffey, Eliot et al. (2010) Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination. Nat Immunol 11:820-6