Gross chromosomal rearrangements are prominent in human cancers, with specific cytogenetic abnormalities contributing to hematopoietic, thyroid, prostate, and lung malignancies. Although the genesis of such chromosomal aberrations is incompletely understood, there is now strong evidence that a particularly dangerous situation arises when DNA double strand breaks (DSBs) occur in proximity to active transcription. These findings suggest that maintenance of genome integrity necessitates coordination between DNA repair and local transcriptional events. We have reported that DSBs silence transcription on contiguous stretches of chromatin in cis to DNA damage sites. Silencing requires ATM kinase activity and histone H2A ubiquitylation. We have extended these findings by discovering that DSB associated SUMOylation is essential for DSB silencing. An interesting observation from these studies is that ATM dependent DSB silencing prevents transcription dependent chromatin movement, a function that may relate to genome integrity control. This proposal utilizes several novel approaches to address two principle questions related to the interplay between DSB chromatin alterations and transcription: (i) How do DSB dependent chromatin alterations contribute to transcriptional gene silencing in cis to DSBs? (ii) Do DSB chromatin alterations promote accurate DNA repair mechanisms by opposing RNAPII driven chromatin movement? Collectively, these questions will address fundamental issues in genome integrity and radiation biology that are related to communication between DSB chromatin responses and transcription.

Public Health Relevance

Gross chromosomal rearrangements are prominent in human cancers, with specific cytogenetic abnormalities contributing to hematopoietic, thyroid, prostate, and lung malignancies. Although the genesis of such chromosomal aberrations is incompletely understood, there is now strong evidence that a particularly dangerous situation arises when DNA double strand breaks (DSBs) occur in proximity to active transcription. These findings suggest that maintenance of genome integrity necessitates coordination between DNA repair and local transcriptional events. This proposal will address fundamental issues in genome integrity and radiation biology that are related to communication between DSB chromatin responses and transcription.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM101149-01A1
Application #
8503908
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Janes, Daniel E
Project Start
2013-06-01
Project End
2017-03-31
Budget Start
2013-06-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$304,000
Indirect Cost
$114,000
Name
University of Pennsylvania
Department
Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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
Fishbein, Lauren; Khare, Sanika; Wubbenhorst, Bradley et al. (2015) Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat Commun 6:6140

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