(modified part is underlined) The Drosophila RNase ZL (dRNaseZ) gene encodes a protein with homologs in all living organisms: bacteria, archaea, and eukarya. All RNase ZL proteins tested so far were found to possess endoribonuclease activity, which is responsible for the removal of a 3'trailer from pre-tRNA. Given that tRNA 3'endonucleolytic activity has been delineated using in vitro, bacterial and cell culture models, it's relevance to RNase ZL function in vivo has yet to be established. Recent studies suggested that RNase ZL might play critical roles in various biological events, including development, disease, cell proliferation, and mitochondrial biogenesis. However, no molecular networks that include RNase ZL have been identified and characterized so far, due in part to a very limited number of model systems studied in vivo. Human ELAC2, a gene that encodes the RNase ZL homolog, has been associated with mitochondria-related diseases and elevated risk of prostate cancer. However, the role of ELAC2 in these processes has not been definitively established. It is not known whether and which of these functions involve RNase ZL endonucleolytic activity. Our long-term objective is to identify developmental events and physiological processes in which RNase ZL is involved, and determine how it contributes to the control of these processes. Previously, we showed that dRNaseZ is an essential gene as its knockout impairs cell growth and proliferation. Based on the preliminary data, we suggest several hypotheses connecting the dRNaseZ function with cell growth and proliferation that will be tested through specific aims formulated in the proposal. First, by studying a collection of EMS-generated mutants we will identify alleles that uncover dRNaseZ functions independent of its role in tRNA processing. Second, using P element mediated transformation we will generate transgenic lines uncoupling nuclear and mitochondrial activities of dRNaseZ. We will test whether dRNaseZ is required to support the integrity of mtDNA and the expression of mitochondrial genes. And finally, we will use a genetic mosaic approach and ectopic expression of aberrant tRNA-precursor to study the role of dRNaseZ in protein synthesis machinery. The knowledge that we expect to gain from Drosophila RNase ZL studies will help better illuminate the possible contribution of its human counterpart to different human disease pathologies.

Public Health Relevance

(no changes) This application targets the Drosophila homolog of human ELAC2/RNase ZL that has been associated with mitochondria-related diseases and elevated risk of prostate cancer. Our ultimate goal is to gain basic information on the biological functions of the RNase ZL gene and to identify molecular networks that it is involved in. The knowledge that we expect to gain from Drosophila RNase ZL studies will help better illuminate the possible contribution of its human counterpart to different human disease pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM097716-01A1
Application #
8232857
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Bender, Michael T
Project Start
2012-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$324,541
Indirect Cost
$124,541
Name
Fordham University
Department
Biology
Type
Other Domestic Higher Education
DUNS #
071011019
City
Bronx
State
NY
Country
United States
Zip Code
10458
Bernardo, Travis J; Dubrovskaya, Veronica A; Xie, Xie et al. (2014) A view through a chromatin loop: insights into the ecdysone activation of early genes in Drosophila. Nucleic Acids Res 42:10409-24
Xie, Xie; Dubrovskaya, Veronica; Yacoub, Nancy et al. (2013) Developmental roles of Drosophila tRNA processing endonuclease RNase ZL as revealed with a conditional rescue system. Dev Biol 381:324-40