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 #
5R01GM101149-02
Application #
8665995
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Willis, Kristine Amalee
Project Start
2013-06-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Harding, Shane M; Greenberg, Roger A (2016) Choreographing the Double Strand Break Response: Ubiquitin and SUMO Control of Nuclear Architecture. Front Genet 7:103
Verma, Priyanka; Greenberg, Roger A (2016) Noncanonical views of homology-directed DNA repair. Genes Dev 30:1138-54
Jiang, Qinqin; Paramasivam, Manikandan; Aressy, Bernadette et al. (2015) MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links. Genes Dev 29:1955-68
Cho, Nam Woo; Greenberg, Roger A (2015) DNA repair: Familiar ends with alternative endings. Nature 518:174-6
Fishbein, Lauren; Khare, Sanika; Wubbenhorst, Bradley et al. (2015) Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat Commun 6:6140
Dilley, Robert L; Greenberg, Roger A (2015) ALTernative Telomere Maintenance and Cancer. Trends Cancer 1:145-156
Sawyer, Sarah L; Tian, Lei; Kähkönen, Marketta et al. (2015) Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov 5:135-42
Harding, Shane M; Boiarsky, Jonathan A; Greenberg, Roger A (2015) ATM Dependent Silencing Links Nucleolar Chromatin Reorganization to DNA Damage Recognition. Cell Rep 13:251-9
Zeqiraj, Elton; Tian, Lei; Piggott, Christopher A et al. (2015) Higher-Order Assembly of BRCC36-KIAA0157 Is Required for DUB Activity and Biological Function. Mol Cell 59:970-83
Li, Mischa L; Yuan, Gang; Greenberg, Roger A (2014) Chromatin yo-yo: expansion and condensation during DNA repair. Trends Cell Biol 24:616-8

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