Mitochondria play an essential role in life and its integrity is a critical issue in organisms. Failure in maintenance of mitochondrial integrity causes numerous diseases including cancer and aging. The mitochondria genome is particularly susceptible to mutations because of its high level of reactive oxygen species (ROS) generated in this organelle, coupled with the low level of DNA repair. Accordingly, about 70% of the mitochondria genome in colon cancers was found with a ROS-related mutation. SUV3 is known to be a component of mitochondrial RNA degradosome. In yeast, inactivation of Suv3 leads to mitochondrial dysfunction and loss of mitochondrial DNA, suggesting that SUV3 is essential for guarding mitochondrial genome stability. However, it is not known what role SUV3 plays in mammals. In our preliminary studies, we showed that inactivation of both SUV3 alleles leads to early mouse embryonic lethality, and that heterozygous mice exhibited an early aging-phenotype, characterized by a shortened life span and predisposition to a broad spectrum of tumors with 90% penetrance, suggesting that SUV3 is a novel tumor suppressor. These diseased phenotypes can be rescued in offspring derived from the cross with wild-type female, but not male mice, suggesting that the major effect of SUV3 is mediated through mitochondria. Consistently, depletion of SUV3 in human cells leads to accumulation of the truncated mitochondrial RNA and an increase of ROS production and apoptosis. Mitochondrial RNA degradation is a tightly monitored process. In E. coli, four major components including RNase E, RhlB, PNPase and enolase constitute the degradosome. In mammals, SUV3 and PNPase were found in mitochondria. Recently, we found that SUV3 has evolutionarily converged both the helicase and the endoribonuclease activities of the primordial degradosome because SUV3, like RhlB, has helicase and ATPase activities and contains an endoribonuclease activity, like RNase E. However, how SUV3 in collaboration with PNPase plays an essential role in mitochondrial RNA degradation and how perturbation of this process contributes to mitochondrial dysfunction leading to cancer or aging phenotype are fascinating questions. In this application, we focus on three specific aims as follows:
Aim 1 is to investigate systematically the premature ageing phenotypes and abnormalities of mitochondrial function of SUV3 heterozygotes.
Aim 2 is to delineate biological and biochemical roles of the conserved domains of SUV3 in RNA degradation.
And Aim 3 is to identify and characterize major components constituting mammalian mitochondrial degradosome as well as to elucidate their contribution in mitochondrial RNA degradation. Results derived from these studies will provide a molecular basis to explain how SUV3 plays a role in aging process and tumorigenesis.

Public Health Relevance

Mitochondrial dysfunction causes numerous diseases including cancer and aging. SUV3 is a component of the mitochondrial RNA degradosome. How SUV3 plays an essential role in mitochondrial RNA degradation and how perturbation of this process contributes to mitochondrial dysfunction leading to cancer and aging phenotype are completely unclear. We plan to use SUV3 heterozygous mice to investigate the abnormalities of mitochondrial RNA degradation. Results derived from these studies will provide a molecular basis to explain how SUV3-mediated RNA degradation plays a role in the aging process and tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG027877-05
Application #
8284339
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Finkelstein, David B
Project Start
2008-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$289,934
Indirect Cost
$94,858
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Wang, Dennis Ding-Hwa; Guo, Xuning Emily; Modrek, Aram Sandaldjian et al. (2014) Helicase SUV3, polynucleotide phosphorylase, and mitochondrial polyadenylation polymerase form a transient complex to modulate mitochondrial mRNA polyadenylated tail lengths in response to energetic changes. J Biol Chem 289:16727-35
Guo, Xuning Emily; Chen, Chi-Fen; Wang, Dennis Ding-Hwa et al. (2011) Uncoupling the roles of the SUV3 helicase in maintenance of mitochondrial genome stability and RNA degradation. J Biol Chem 286:38783-94
Wang, Dennis Ding-Hwa; Shu, Zhanyong; Lieser, Scot A et al. (2009) Human mitochondrial SUV3 and polynucleotide phosphorylase form a 330-kDa heteropentamer to cooperatively degrade double-stranded RNA with a 3'-to-5'directionality. J Biol Chem 284:20812-21
Khidr, Lily; Wu, Guikai; Davila, Antonio et al. (2008) Role of SUV3 helicase in maintaining mitochondrial homeostasis in human cells. J Biol Chem 283:27064-73