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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095641-10
Application #
8266337
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2002-05-01
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$267,622
Indirect Cost
$98,241
Name
University of Texas MD Anderson Cancer Center
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Huang, Ting-Hsiang; Fowler, Faith; Chen, Chin-Chuan et al. (2018) The Histone Chaperones ASF1 and CAF-1 Promote MMS22L-TONSL-Mediated Rad51 Loading onto ssDNA during Homologous Recombination in Human Cells. Mol Cell 69:879-892.e5
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Fowler, Faith; Tyler, Jessica K (2017) Anchoring Chromatin Loops to Cancer. Dev Cell 42:209-211
Aguilar, Rhiannon R; Tyler, Jessica K (2017) Thinking Outside the Cell: Replicating Replication In Vitro. Mol Cell 65:5-7
Diao, Li-Ting; Chen, Chin-Chuan; Dennehey, Briana et al. (2017) Delineation of the role of chromatin assembly and the Rtt101Mms1 E3 ubiquitin ligase in DNA damage checkpoint recovery in budding yeast. PLoS One 12:e0180556
Wang, Pingping; Byrum, Stephanie; Fowler, Faith C et al. (2017) Proteomic identification of histone post-translational modifications and proteins enriched at a DNA double-strand break. Nucleic Acids Res 45:10923-10940
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

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