Mechanisms of arsenic-induced chromosomal instability and carcinogenesis

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DESCRIPTION (provided by applicant): Chronic exposure to arsenic is highly associated with the occurrence of several types of malignancies, including skin, lung and bladder cancer. Despite extensive studies in the past, the mechanism by which arsenic compounds promote carcinogenesis remains largely unclear. Epidemiological studies reveal that arsenic exposure induces the formation of micronuclei, chromosomal aberrations, and aneuploidy, which may be a culprit in the genesis of cancer since most solid tumors are aneuploid. High fidelity DNA replication and faithful distribution of the chromosomal complement to daughter cells during cell division are of paramount importance to the maintenance of chromosomal stability. We previously demonstrated that arsenic trioxide [As(III)] compromises paclitaxel-induced mitotic arrest in both p53-deficient and proficient cells. We have recently shown that As(III) induces chromosomal instability by suppressing the activation of BubR1, a cell cycle checkpoint protein, leading to unscheduled activation of anaphase promoting complex/cyclosome (APC/C) in melanoma and HeLa cells. Activated APC/C apparently causes premature separation of sister chromatids, aberrant sister chromatid exchanges, and diplochromosome formation in cells with wild-type p53. Moreover, mice with haploinsufficiency of BubR1 are prone to the development of skin lesions (hyperplasia) after exposure to UV irradiation. Given the documented effect of As(III) on the induction of nuclear abnormalities, we hypothesize that As(III) compromises the BubR1-dependent spindle checkpoint, resulting in unscheduled activation of APC/C, chromosomal instability, and neoplastic transformation owing to dysregulation of DNA replication and chromosome segregation processes. To test this hypothesis, we will (1) elucidate the molecular basis by which As(III) induces chromosomal instability with an emphasis on studying the Emi1->APC/C->geminin->Cdt1 regulatory axis, (2) determine if As(III) synergizes with spindle checkpoint deficiency in promoting chromosomal instability and oncogenic transformation in vitro, (3) determine if As(III) enhances spontaneous tumor development in BubR1 haploinsufficient mice and investigate if As(III) functions as a co-carcinogen in promoting skin tumorigenesis induced by UV irradiation in these mice. The long term goal of the project is to understand whether the biological properties associated with As(III) are at least partly due to its action on the perturbation of APC/C activities, causing deregulation of proteins crucial for the control of DNA replication and chromosomal segregation during cell division. We anticipate that this line of research will lead to the identification of key molecular targets for cancer intervention, as well as for ameliorating the detrimental effects of arsenic compounds.