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Ataxia-Telangiectasia Mutated Interferes with Adenovirus Early Region 4 Mutant DNA Replication

Gautam, Dipendra

Abstract Details

2013, Doctor of Philosophy, Miami University, Microbiology.
The integrity of eukaryotic genomes is maintained by sophisticated networks of DNA damage mediator and effector proteins. Upon DNA damage, a well-orchestrated DNA damage response (DDR) is initiated by proteins that block cell cycle progression and repair the DNA or induce apoptosis as a last resort. DNA damage is sensed by a sensor complex composed of the Mre11/Rad50/Nbs1 (MRN) proteins that relay the damage signal to activate ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR) kinases. These central kinases phosphorylate numerous DNA repair proteins and checkpoint kinases. In addition, DNA repair proteins are recruited to the site of DNA damage resulting in the formation of distinct nuclear foci. These signaling networks also respond to Adenovirus (Ad) infection and could potentially interfere with a productive life cycle. In wild type Ad infections, early region 4 gene products target Mre11 for degradation thereby interfering with its ability to sense DNA damage and activate phosphorylation cascades important during DNA repair. E4 mutants that lack these regulatory proteins activate a DNA damage response (DDR), which in turn interferes with a productive viral infection. E4 mutant phenotypes include genome concatemer formation and defective viral DNA and late protein synthesis. E4 mutant growth defects are substantially rescued in cells lacking a functional MRN complex; however the mechanism by which the MRN complex interferes with E4 mutant DNA replication is unknown. We investigated the role of ATM and ATR in interfering with a productive E4 mutant infection. We did not identify a role for ATM and ATR in E4 mutant genome concatenation. In contrast, E4 mutant DNA replication centers were well developed and DNA replication was rescued in cells that lack ATM or in cells treated with ATM kinase inhibitors. Our data show that the MRN complex inhibits E4 mutant DNA replication through its ability to activate ATM, which interferes with E4 mutant DNA replication by localizing to viral replication centers. Further we found that ATM-dependent recruitment of late DDR proteins including RNF8 and 53BP1 correlates with the poor development of replication centers. In conclusion, ATM plays an important role in activating DNA damage responses that interfere with viral DNA replication.
Eileen Bridge, Ph.D. (Advisor)
Gary Janssen, Ph.D. (Committee Chair)
Joseph Carlin, Ph.D. (Committee Member)
Xiao-Wen Cheng, Ph.D. (Committee Member)
David Pennock, Ph.D. (Committee Member)
113 p.

Recommended Citations

Citations

  • Gautam, D. (2013). Ataxia-Telangiectasia Mutated Interferes with Adenovirus Early Region 4 Mutant DNA Replication [Doctoral dissertation, Miami University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=miami1380203718

    APA Style (7th edition)

  • Gautam, Dipendra. Ataxia-Telangiectasia Mutated Interferes with Adenovirus Early Region 4 Mutant DNA Replication. 2013. Miami University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=miami1380203718.

    MLA Style (8th edition)

  • Gautam, Dipendra. "Ataxia-Telangiectasia Mutated Interferes with Adenovirus Early Region 4 Mutant DNA Replication." Doctoral dissertation, Miami University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=miami1380203718

    Chicago Manual of Style (17th edition)