During growth and division of cells in the body, the DNA at the ends of chromosomes becomes shorter owing to an inability of cells to fully replicate these sites, which are called telomeres. Excessively short telomeres are dysfunctional and cause cells to stop dividing, and in many cases commit suicide. Thus, telomere shortening provides a "timer" that limits the growth potential of most cells in the body. How cells escape this limit is a critical question for understanding the genesis of cancer. The work proposed here uses the fruitfly, Drosophila melanogaster, as a model system to identify the genetic mechanisms either guide cells to suicide, or allow them to escape that fate. Specially engineered chromosomes are used to provide a system that efficiently, and on command, causes loss of one telomere in a cell. Most cells die in response, but a few cells escape and divide repeatedly. The experiments described in this proposal will define the mechanisms that cells use to escape death, providing important insight into the earliest stages of carcinogenesis. In reproductive cells, the loss of a telomere is often followed by construction of a new telomere. The proposed work will define the genetic control over this chromosome healing. Inappropriately healed chromosomes are associated with a number of human disorders. Moreover, healing is a common feature of cancer cells, adding further relevance to human health.
The first part of this work will define the mechanisms that cells use to escape the normal limits to growth when faced with unrepairable DNA damage. The second part will identify the genetic regulators of these mechanisms. The third part will determine how these genetic controls interact to control cell fate. Understanding the genes that control these processes may lead to prevention or treatment of cancer or inherited chromosomal deficiencies.
|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|
|Golic, Mary M; Golic, Kent G (2011) A simple and rapid method for constructing ring-X chromosomes in Drosophila melanogaster. Chromosoma 120:159-64|
|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|
|Titen, Simon W A; Golic, Kent G (2010) Healing of euchromatic chromosome breaks by efficient de novo telomere addition in Drosophila melanogaster. Genetics 184:309-12|
|Titen, Simon W A; Golic, Kent G (2008) Telomere loss provokes multiple pathways to apoptosis and produces genomic instability in Drosophila melanogaster. Genetics 180:1821-32|
|Diaz-Castillo, Carlos; Golic, Kent G (2007) Evolution of gene sequence in response to chromosomal location. Genetics 177:359-74|
|Gong, Wei J; Golic, Kent G (2006) Loss of Hsp70 in Drosophila is pleiotropic, with effects on thermotolerance, recovery from heat shock and neurodegeneration. Genetics 172:275-86|
|Maggert, Keith A; Golic, Kent G (2005) Highly efficient sex chromosome interchanges produced by I-CreI expression in Drosophila. Genetics 171:1103-14|
|Xie, Heng B; Golic, Kent G (2004) Gene deletions by ends-in targeting in Drosophila melanogaster. Genetics 168:1477-89|
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