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)
Type
Research Project (R01)
Project #
5R01GM059691-16
Application #
8722569
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Willis, Kristine Amalee
Project Start
Project End
Budget Start
Budget End
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
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 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; 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
Lopez-Mosqueda, Jaime; Maas, Nancy L; Jonsson, Zophonias O et al. (2010) Damage-induced phosphorylation of Sld3 is important to block late origin firing. Nature 467:479-83
Lopez-Mosqueda, Jaime; Vidanes, Genevieve M; Toczyski, David P (2010) Cdc5 blocks in vivo Rad53 activity, but not in situ activity (ISA). Cell Cycle 9:4266-8
Bonilla, Carla Yaneth; Melo, Justine Amy; Toczyski, David Paul (2008) Colocalization of sensors is sufficient to activate the DNA damage checkpoint in the absence of damage. Mol Cell 30:267-76
Kaye, Julia A; Melo, Justine A; Cheung, Stephanie K et al. (2004) DNA breaks promote genomic instability by impeding proper chromosome segregation. Curr Biol 14:2096-106
Thornton, Brian R; Toczyski, David P (2003) Securin and B-cyclin/CDK are the only essential targets of the APC. Nat Cell Biol 5:1090-4
Galgoczy, D J; Toczyski, D P (2001) Checkpoint adaptation precedes spontaneous and damage-induced genomic instability in yeast. Mol Cell Biol 21:1710-8

Showing the most recent 10 out of 11 publications