Multiple Pathways for Repair of DNA Double-Strand Breaks in Mammalian Chromosomes

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Molecular and Cellular Biology, December 1999, p. 8353-8360, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Multiple Pathways for Repair of DNA Double-Strand Breaks in Mammalian Chromosomes

Yunfu Lin, Tamas Lukacsovich, and Alan S. Waldman^*

Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208

Received 30 April 1999/Returned for modification 10 June 1999/Accepted 9 September 1999

To study repair of DNA double-strand breaks (DSBs) in mammalian chromosomes, we designed DNA substrates containing a thymidinekinase (TK) gene disrupted by the 18-bp recognition site for yeastendonuclease I-SceI. Some substrates also contained a second defectiveTK gene sequence to serve as a genetic donor in recombinationalrepair. A genomic DSB was induced by introducing endonucleaseI-SceI into cells containing a stably integrated DNA substrate.DSB repair was monitored by selection for TK-positive segregants.We observed that intrachromosomal DSB repair is accomplished withnearly equal efficiencies in either the presence or absence ofa homologous donor sequence. DSB repair is achieved by nonhomologousend-joining or homologous recombination, but rarely by nonconservativesingle-strand annealing. Repair of a chromosomal DSB by homologousrecombination occurs mainly by gene conversion and appears torequire a donor sequence greater than a few hundred base pairsin length. Nonhomologous end-joining events typically involveloss of very few nucleotides, and some events are associated withgene amplification at the repaired locus. Additional studies revealedthat precise religation of DNA ends with no other concomitantsequence alteration is a viable mode for repair of DSBs in a mammaliangenome.

^* Corresponding author. Mailing address: Dept. of Biological Sciences, University of South Carolina, 700 Sumter St., Columbia,SC 29208. Phone: (803) 777-8405. Fax: (803) 777-4002. E-mail:awaldman{at}sc.edu.

Molecular and Cellular Biology, December 1999, p. 8353-8360, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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