Radiation-induced double-strand breaks (DSBs) are fundamental threats to genomic integrity that result in genomic instability if not properly repaired, which can in turn lead to cancer and cell death. Although we know a great deal about the pathways of DSB repair, we know very little about how DSB repair occurs in its natural context in the cell, that is, chromatin. Chromatin by its very nature is an impediment for proteins accessing the DNA, yet the repair machinery is somehow able to navigate through the chromatin and successfully repair DNA damage. Chromatin also plays a key role in transducing the cell's response to DNA damage via the DNA damage cell cycle checkpoint. Until recently, there has been a large gap in our understanding as to how the DNA damage checkpoint is turned off in order to allow cells to reenter the cell cycle and survive after DNA repair is complete. Integral to this process is the way that the cell senses that DNA repair is complete, which has also been a long-standing mystery. We have recently discovered that the restoration of the chromatin structure over the newly-repaired DNA, rather than DNA repair itself, is the elusive signal for inactivation, or "recovery" of the DNA damage checkpoint (Chen et al., Cell 2008) in order to allow cell survival after DSB repair. Although our studies have revealed a novel link between chromatin structure, checkpoint recovery and cell cycle re-entry after DNA repair, many questions remain to be answered. The proposed studies will uncover the elusive mechanism used by eukaryotic cells to turn off the DNA damage checkpoint after DNA repair is complete. By elucidating the mechanism whereby restoration of chromatin carrying this specific histone modification signals to the DNA damage checkpoint machinery that DNA repair is complete, we hope to fill significant gaps in our current knowledge of the chromosomal repair process. We will also identify novel proteins involved in turning off the DNA damage checkpoint that will be novel targets for therapeutic intervention in order to prevent inactivation of the damage checkpoint after irradiation of cancer cells, in order to prevent cancer cells from dividing.
Radiation-induced double-strand breaks (DSBs) are fundamental threats to genomic integrity that result in genomic instability if not properly repaired, which can in turn lead to cancer and cell death. These studies will fill significant gaps in our current knowledge of the chromosomal repair process following radiation exposure. We will also identify novel targets for therapeutic intervention in order to prevent inactivation of the damage checkpoint after radiation therapy of cancer cells, in order to prevent cancer cells from dividing.
|Pal, Sangita; Tyler, Jessica K (2016) Epigenetics and aging. Sci Adv 2:e1600584|
|Graves, Hillary K; Wang, Pingping; Lagarde, Matthew et al. (2016) Mutations that prevent or mimic persistent post-translational modifications of the histone H3 globular domain cause lethality and growth defects in Drosophila. Epigenetics Chromatin 9:9|
|Li, Xuan; Tyler, Jessica K (2016) Nucleosome disassembly during human non-homologous end joining followed by concerted HIRA- and CAF-1-dependent reassembly. Elife 5:|
|Wike, Candice L; Graves, Hillary K; Hawkins, Reva et al. (2016) Aurora-A mediated histone H3 phosphorylation of threonine 118 controls condensin I and cohesin occupancy in mitosis. Elife 5:e11402|
|Chen, Kaifu; Hu, Zheng; Xia, Zheng et al. (2016) The Overlooked Fact: Fundamental Need for Spike-In Control for Virtually All Genome-Wide Analyses. Mol Cell Biol 36:662-7|
|Wike, Candice L; Graves, Hillary K; Wason, Arpit et al. (2016) Excess free histone H3 localizes to centrosomes for proteasome-mediated degradation during mitosis in metazoans. Cell Cycle 15:2216-2225|
|Lee, Siu Sylvia; Tyler, Jessica K (2016) Physiology: Stressed-out chromatin promotes longevity. Nature 534:625-6|
|Tyler, Jessica K (2016) Nucleosomes Find Their Place in Life. Trends Genet 32:689-690|
|Zhan, Yanai; Kost-Alimova, Maria; Shi, Xi et al. (2015) Development of novel cellular histone-binding and chromatin-displacement assays for bromodomain drug discovery. Epigenetics Chromatin 8:37|
|Johnson, Danielle P; Spitz, Gabriella S; Tharkar, Shweta et al. (2015) HDAC1,2 inhibition impairs EZH2- and BBAP-mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma. Oncotarget 6:4863-87|
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