Many cancers accumulate mutations in genes that alter the normal activities of the proteins they encode to promote tumor formation and growth. Recently, cancer-causing mutations in genes encoding histone proteins were discovered in a wide array of cancers. We found that some of the mutations in the "oncohistones" disrupt amino acids that are chemically modified by a protein called PARP-1 through a process called ADP-ribosylation (ADPRylation). Loss of ADPRylation in the oncohistones allows the cancer cells to escape growth inhibition mediated by ADPRylation. Moreover, it may also render the cancer cells resistant to the therapeutic effects of PARP inhibitors, a novel class of cancer drug...

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Many cancers accumulate mutations in genes that alter the normal activities of the proteins they encode to promote tumor formation and growth. Recently, cancer-causing mutations in genes encoding histone proteins were discovered in a wide array of cancers. We found that some of the mutations in the "oncohistones" disrupt amino acids that are chemically modified by a protein called PARP-1 through a process called ADP-ribosylation (ADPRylation). Loss of ADPRylation in the oncohistones allows the cancer cells to escape growth inhibition mediated by ADPRylation. Moreover, it may also render the cancer cells resistant to the therapeutic effects of PARP inhibitors, a novel class of cancer drugs. Thus, the use of PARP inhibitors in some patients with oncohistone mutations in their cancers may have unintended, and perhaps even harmful, consequences.

In this research proposal, we propose a series of experiments to test the hypothesis that cancers accumulate mutations at ADPRylation sites on histones to circumvent the normal growth regulatory processes that keep tumor formation in check. In addition, we will explore the molecular mechanisms of this regulation in breast and ovarian cancers, as well as the implications for the use of PARP inhibitors in cancers containing oncohistone mutants. Successful completion of the proposed experiments will yield (1) new resources for the research community, (2) new insights about the molecular underpinnings of cancer, and (3) new methods and approaches for studying cancer.

Collectively, our proposed experiments will address a new, unique, and clinically-relevant set of molecular questions about (1) the function of oncohistones as drivers of carcinogenesis, (2) the molecular mechanisms governing oncohistone function, (3) the role of PARP-1 in chromatin structure and gene regulation, and (4) the mechanisms of PARP inhibitor resistance in cancers.

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