Despite extensive study of DNA damage responses in both normal and pathologic settings, it is poorly understood how chromatin reorganization occurs in response to DNA double-strand breaks (DSBs) and contributes to genome maintenance and cancer cell fitness. There is now strong evidence that DSB responses promote changes in higher order chromatin structure. These arise in part by DSB dependent alterations in transcription, and by DSB induced recombination between homologous genomic regions on different chromosomes. This proposal utilizes several novel approaches to address questions related to the interplay between DSB chromatin alterations and genome integrity. Namely, (i) How do DSB dependent chromatin alterations contribute to transcriptional gene silencing in cis to DSBs, and (ii) how do DSB induced inter-chromosomal telomere associations contribute to genome integrity and survival? Collectively, these investigations will address fundamental issues in genome integrity and radiation biology that are related to communication between DSB responses and higher order chromatin structure.

Public Health Relevance

Despite extensive study of DNA damage responses in both normal and pathologic settings, it is poorly understood how chromatin reorganization occurs in response to DNA double-strand breaks (DSBs) and contributes to genome maintenance and cancer cell fitness. My group has shown that DSB responses promote ATM dependent alterations in transcription, and recombination dependent changes in higher order chromatin associations. We propose to use novel experimental systems to address how higher order chromatin changes are enacted by DNA damage responses, and how they impact genome integrity and survival to DSBs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101149-06
Application #
9481836
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Willis, Kristine Amalee
Project Start
2013-06-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Harding, Shane M; Benci, Joseph L; Irianto, Jerome et al. (2017) Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548:466-470
Irianto, Jerome; Xia, Yuntao; Pfeifer, Charlotte R et al. (2017) As a Nucleus Enters a Small Pore, Chromatin Stretches and Maintains Integrity, Even with DNA Breaks. Biophys J 112:446-449
Cho, Nam Woo; Lampson, Michael A; Greenberg, Roger A (2017) In vivo imaging of DNA double-strand break induced telomere mobility during alternative lengthening of telomeres. Methods 114:54-59
Irianto, Jerome; Xia, Yuntao; Pfeifer, Charlotte R et al. (2017) DNA Damage Follows Repair Factor Depletion and Portends Genome Variation in Cancer Cells after Pore Migration. Curr Biol 27:210-223
Zahn, Karl E; Greenberg, Roger A (2017) Putting PHDs to work: PHF11 clears the way for EXO1 in double-strand break repair. Genes Dev 31:3-5
Irianto, Jerome; Pfeifer, Charlotte R; Bennett, Rachel R et al. (2016) Nuclear constriction segregates mobile nuclear proteins away from chromatin. Mol Biol Cell 27:4011-4020
Verma, Priyanka; Greenberg, Roger A (2016) Noncanonical views of homology-directed DNA repair. Genes Dev 30:1138-54
Dilley, Robert L; Verma, Priyanka; Cho, Nam Woo et al. (2016) Break-induced telomere synthesis underlies alternative telomere maintenance. Nature 539:54-58
Harding, Shane M; Greenberg, Roger A (2016) Choreographing the Double Strand Break Response: Ubiquitin and SUMO Control of Nuclear Architecture. Front Genet 7:103
Cho, Nam Woo; Greenberg, Roger A (2015) DNA repair: Familiar ends with alternative endings. Nature 518:174-6

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