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

Lead Research Organisation: University of Oxford
Department Name: UNLISTED

Abstract

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.

Technical Summary

Histone H3 lysine 36 (H3K36) methylation plays a central role in both orchestrating the DNA damage response (DDR) and in suppressing tumorigenesis. We have discovered key roles for H3K36 trimethylation (H3K36me3) in the DDR where it both promotes homologous recombination (HR) repair of DNA double-strand breaks (DSBs) (Pfister et al., Cell Reports 2014), and is also essential for DNA replication restart following replication stress resulting from checkpoint kinase inactivation (Pfister et al., Cancer Cell 2015). Accordingly SETD2-dependent H3K36me3 is frequently depleted in a number of cancer types, including high-grade pediatric gliomas (>50%), and metastatic renal carcinomas (~60%), for which prognosis is poor. We recently exploited a conserved synthetic lethal relationship we identified in fission yeast to target H3K36me3-deficient cancers, using the WEE1 inhibitor, AZD1775, which is already in Phase II clinical trials. As a result of these studies, together with the development of a biomarker to detect H3K36me3 loss in patient tissue, the use of AZD1775 to target H3K36me3-deficient cancers has now been adopted into the MRC-supported FOCUS4 clinical trial. Despite these advances, how H3K36me3 coordinates these distinct DDR functions is unknown. Moreover, the extent to which this synthetic lethal relationship can be expanded and translated into the clinic has not yet been explored. We therefore propose to determine how H3K36me3 maintains viability in response to replication stress, thereby better understanding this synthetic lethality (Aim 1); to delineate the role of the H3K36me3 pathway in homologous recombination repair (Aim 2); and to further translate these findings into the clinic through identifying other targetable disease sites, by determining the AZD1775 sensitivity of cancers with intermediate H3K36me3 levels, by improving cancer targeting through combining AZD1775 with other agents, including ionizing radiation, and by understanding the mechanisms and pathways leading to AZD1775 resistance (Aim 3). We will use a powerful combination of yeast and mammalian genetics, together with small molecular inhibitors to achieve these aims. We anticipate that the proposed research will provide mechanistic insights into how histone H3K36 trimethylation promotes DSB repair and maintains cell viability in response to such replication stress. Further, we predict that by expanding this synthetic lethal relationship through genetic triangulation we will broaden both the biological and clinical application of our findings.

Publications

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