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Originally published as Genetics Published Articles Ahead of Print on May 4, 2007.
Genetics, Vol. 176, 1441-1451, July 2007, Copyright © 2007
doi:10.1534/genetics.107.073635
Reducing DNA Polymerase 
in the Absence of Drosophila ATR Leads to P53-Dependent Apoptosis and Developmental Defects
Jeannine R. LaRocque*,
Diana L. Dougherty*,1,
Sumreen K. Hussain* and
Jeff Sekelsky*,
,2
* Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599 and Program in Molecular Biology and Biotechnology, University of North Carolina, Chapel Hill, North Carolina 27599
2 Corresponding author: Department of Biology, CB#3280, University of North Carolina, Chapel Hill, NC 27599.
E-mail: sekelsky{at}unc.edu
The ability to respond to DNA damage and incomplete replication ensures proper duplication and stability of the genome. Two checkpoint kinases, ATM and ATR, are required for DNA damage and replication checkpoint responses. In Drosophila, the ATR ortholog (MEI-41) is essential for preventing entry into mitosis in the presence of DNA damage. In the absence of MEI-41, heterozygosity for the E(mus304) mutation causes rough eyes. We found that E(mus304) is a mutation in DNApol-
180, which encodes the catalytic subunit of DNA polymerase . We did not find any defects resulting from reducing Pol by itself. However, reducing Pol in the absence of MEI-41 resulted in elevated P53-dependent apoptosis, rough eyes, and increased genomic instability. Reducing Pol in mutants that lack downstream components of the DNA damage checkpoint (DmChk1 and DmChk2) results in the same defects. Furthermore, reducing levels of mitotic cyclins rescues both phenotypes. We suggest that reducing Pol slows replication, imposing an essential requirement for the MEI-41-dependent checkpoint for maintenance of genome stability, cell survival, and proper development. This work demonstrates a critical contribution of the checkpoint function of MEI-41 in responding to endogenous damage.