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Originally published as Genetics Published Articles Ahead of Print on March 21, 2005.
Genetics, Vol. 170, 355-363, May 2005, Copyright © 2005
doi:10.1534/genetics.104.039362
A Role for DNA Mismatch Repair Protein Msh2 in Error-Prone Double-Strand-Break Repair in Mammalian Chromosomes
Jason A. Smith, Barbara Criscuolo Waldman and Alan S. Waldman1
Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208
1 Corresponding author: Department of Biological Sciences, University of South Carolina, 700 Sumter St., Columbia, SC 29208.
E-mail: awaldman{at}sc.edu
We examined error-prone nonhomologous end joining (NHEJ) in Msh2-deficient and wild-type Chinese hamster ovary cell lines. A DNA substrate containing a thymidine kinase (tk) gene fused to a neomycin-resistance (neo) gene was stably integrated into cells. The fusion gene was rendered nonfunctional due to a 22-bp oligonucleotide insertion, which included the 18-bp I-SceI endonuclease recognition site, within the tk portion of the fusion gene. A double-strand break (DSB) was induced by transiently expressing the I-SceI endonuclease, and deletions or insertions that restored the tk-neo fusion gene's reading frame were recovered by selecting for G418-resistant colonies. Overall, neither the frequency of recovery of G418-resistant colonies nor the sizes of NHEJ-associated deletions were substantially different for the mutant vs. wild-type cell lines. However, we did observe greater usage of terminal microhomology among NHEJ events recovered from wild-type cells as compared to Msh2 mutants. Our results suggest that Msh2 influences error-prone NHEJ repair at the step of pairing of terminal DNA tails. We also report the recovery from both wild-type and Msh2-deficient cells of an unusual class of NHEJ events associated with multiple deletion intervals, and we discuss a possible mechanism for the generation of these "discontinuous deletions."
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