Understanding how genome stability is maintained in response to chromosomal breaks.

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DNA is wrapped around proteins called histones. Histones are modified in a number of ways that can affect cellular processes. We found that a particular histone modification, histone H3 lysine 36 trimethylation (H3K36me3), plays a key role in promoting accurate repair of broken chromosomes using a mechanism called homologous recombination. This histone mark is also essential for restarting DNA replication after exposure to replication stress, which is commonly observed in cancer cells. Moreover, we found a way to specifically target cancer cells which have lost this histone mark, using a drug (AZD1775), which is already in Phase II clinical trials. Our approach has now entered clinical trials. We plan to determine how H3K36me3 maintains viability in response to replication stress (Aim 1); how it promotes homologous recombination repair (Aim 2); and to further translate these findings into the clinic (Aim 3). We predict this work will advance our understanding of how H3K36me3 maintains genome stability in response to replication stress, and ionizing radiation; and will improve the targeting of cancers in which this histone mark is frequently depleted, including high-grade pediatric gliomas (>50%), metastatic renal carcinomas (~60%), for which prognosis is poor, and potentially other cancer types.