The loss of telomeric DNA in human somatic cells, arising from of the lack of telomerase expression, causes cellular senescesce and is associated with aging. Escaping the normal consequences of telomere loss is a critical step in the progression of cancer. Thus, understanding the normal mechanisms of cellular response to telomere loss and mechanisms that bypass the normal response are important for understanding, and possibly treating, cancer and ailments associated with aging. This work will use the model organism Drosophila melanogaster to investigate these issues. Preliminary experiments show that the response of Drosophila cells to telomere loss is very similar of the response of human cells to telomere loss, and is likely to be highly informative. There are 4 primary goals of this work. The first goal is to quantitatively characterize the response of Drosophila somatic cells to loss of a single telomere. A method for tracking the fate of cells that have lost a telomere will be implemented for this purpose. Second, the genetic control of these responses will be investigated. The third goal is to determine the mechanism of response of male germline cells, in which the non-telomeric chromosome ends are efficiently healed. The final goal is to investigate the nature of the healed chromosomes, to determine whether the telomeres they posses provide a normal protective function to the end of the chromosomes, or whether they are only partially functional. These investigations will provide an understanding of the machinery used to recognize telomere loss and to direct the response of cells to such loss. The differences between somatic and germline cells may provide insight into similar differences found in human cells. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM065604-06A1
Application #
7146621
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Carter, Anthony D
Project Start
2001-09-01
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
6
Fiscal Year
2006
Total Cost
$310,213
Indirect Cost
Name
University of Utah
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Karg, Travis J; Golic, Kent G (2018) Photoconversion of DAPI and Hoechst dyes to green and red-emitting forms after exposure to UV excitation. Chromosoma 127:235-245
Kurzhals, Rebeccah L; Fanti, Laura; Ebsen, A C Gonzalez et al. (2017) Chromosome Healing Is Promoted by the Telomere Cap Component Hiphop in Drosophila. Genetics 207:949-959
Rong, Yikang S; Golic, Mary M; Golic, Kent G (2016) The pugilistDominant Mutation of Drosophila melanogaster: A Simple-Sequence Repeat Disorder Reveals Localized Transport in the Eye. PLoS One 11:e0151377
Chakraborty, Riddhita; Li, Ying; Zhou, Lei et al. (2015) Corp Regulates P53 in Drosophila melanogaster via a Negative Feedback Loop. PLoS Genet 11:e1005400
Akbari, Omar S; Bellen, Hugo J; Bier, Ethan et al. (2015) BIOSAFETY. Safeguarding gene drive experiments in the laboratory. Science 349:927-9
Hill, Hunter; Golic, Kent G (2015) Preferential Breakpoints in the Recovery of Broken Dicentric Chromosomes in Drosophila melanogaster. Genetics 201:563-72
Titen, Simon W A; Lin, Ho-Chen; Bhandari, Jayaram et al. (2014) Chk2 and p53 regulate the transmission of healed chromosomes in the Drosophila male germline. PLoS Genet 10:e1004130
Golic, Kent G (2013) RNA-guided nucleases: a new era for engineering the genomes of model and nonmodel organisms. Genetics 195:303-8
Kurzhals, Rebeccah L; Titen, Simon W A; Xie, Heng B et al. (2011) Chk2 and p53 are haploinsufficient with dependent and independent functions to eliminate cells after telomere loss. PLoS Genet 7:e1002103
Golic, Mary M; Golic, Kent G (2011) A simple and rapid method for constructing ring-X chromosomes in Drosophila melanogaster. Chromosoma 120:159-64

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