Genome Instability in Tumorigenesis
The role of nuclear architecture in oncogenic genome instability
An emerging picture of oncogenic genome instability indicates that nuclear architecture influences oncogenic instability by favoring certain chromosomal translocations while disfavoring others. This model posits that non-random distribution of chromosomes within the nuclear volume results in proximity of certain chromosome pairs, and thus predisposes these pairs to involvement in translocations. We are examining how nuclear architecture influences the acquisition of characteristic chromosome abnormalities in NHEJ Trp53-deficient lymphomas. A major goal is to elucidate the mechanisms for oncogenic chromosomal translocations and to understand the molecular etiology of complex cytogenetic features commonly seen in cancer.
New mouse tumor models
With the exception of medulloblastomas, NHEJ Trp53 doubly-deficient animals do not develop other malignancies. This narrow tumor spectrum is surprising because NHEJ is required for V(D)J recombination in T, as well as B cells, and functions in general genome stability in many, if not all, somatic cells. It was reasoned that lack of the Jh region should prevent or delay pro-B cell tumorigenesis, and possibly allow the development of tumors in other cell types. Such non-B lineage tumors may represent important new mouse cancer models, and will be a valuable resource in evaluating the role of DSB repair in tumor suppression in other tissues.
