During genotoxic stress, cells activate a pathway, called the DNA damage checkpoint, to signal that damage has occurred. The inactivation of this checkpoint pathway is associated with many types of cancer, especially lymphoma and leukemia. The great majority of these checkpoint genes are conserved from humans to yeast. In fact, many of these genes have human homologs implicated in tumorigenesis. This application proposes to examine the ways in which the DNA damage checkpoint impinges upon normal cellular physiology, and the repercussions of DNA damage when the pathway is not functioning correctly. We will continue our previous studies in which we identified proteins that are modified by phosphorylation and ubiquitination when cells are damaged. We will also expand upon these studies by determining the significance of these events and the mechanisms by which they alter protein function.

Public Health Relevance

. Cancer is the result of uncontrolled cell division and is often initiated by mutations resulting from DNA damage. In this proposal, we outline experiments that characterize proteins responsible for regulating cell division in response to DNA damage. In doing this, we can better understand how cancers arise and the characteristics of tumors that can be used to selectively target them.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059691-16
Application #
8722569
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Willis, Kristine Amalee
Project Start
1999-08-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Mark, Kevin G; Loveless, Theresa B; Toczyski, David P (2016) Isolation of ubiquitinated substrates by tandem affinity purification of E3 ligase-polyubiquitin-binding domain fusions (ligase traps). Nat Protoc 11:291-301
Edenberg, Ellen R; Mark, Kevin G; Toczyski, David P (2015) Ndd1 turnover by SCF(Grr1) is inhibited by the DNA damage checkpoint in Saccharomyces cerevisiae. PLoS Genet 11:e1005162
Downey, Michael; Johnson, Jeffrey R; Davey, Norman E et al. (2015) Acetylome profiling reveals overlap in the regulation of diverse processes by sirtuins, gcn5, and esa1. Mol Cell Proteomics 14:162-76
Loveless, Theresa B; Topacio, Benjamin R; Vashisht, Ajay A et al. (2015) DNA Damage Regulates Translation through β-TRCP Targeting of CReP. PLoS Genet 11:e1005292
Edenberg, Ellen R; Vashisht, Ajay A; Topacio, Benjamin R et al. (2014) Hst3 is turned over by a replication stress-responsive SCF(Cdc4) phospho-degron. Proc Natl Acad Sci U S A 111:5962-7
Edenberg, Ellen R; Downey, Michael; Toczyski, David (2014) Polymerase stalling during replication, transcription and translation. Curr Biol 24:R445-52
Edenberg, Ellen R; Vashisht, Ajay; Benanti, Jennifer A et al. (2014) Rad53 downregulates mitotic gene transcription by inhibiting the transcriptional activator Ndd1. Mol Cell Biol 34:725-38
Downey, Michael; Knight, Britta; Vashisht, Ajay A et al. (2013) Gcn5 and sirtuins regulate acetylation of the ribosomal protein transcription factor Ifh1. Curr Biol 23:1638-48
Berens, Theresa J; Toczyski, David P (2012) Keeping it together in times of stress: checkpoint function at stalled replication forks. Mol Cell 45:585-6
Berens, Theresa J; Toczyski, David P (2012) Colocalization of Mec1 and Mrc1 is sufficient for Rad53 phosphorylation in vivo. Mol Biol Cell 23:1058-67

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