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Molecular and Cellular Biology, December 2000, p. 9068-9075, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Coupled Homologous and Nonhomologous Repair of a Double-Strand Break Preserves Genomic Integrity in Mammalian Cells

Christine Richardson and Maria Jasin*

Cell Biology Program, Memorial Sloan-Kettering Cancer Center, and Cornell University Graduate School of Medical Sciences, New York, New York 10021

Received 11 August 2000/Returned for modification 7 September 2000/Accepted 12 September 2000

DNA double-strand breaks (DSBs) may be caused by normal metabolic processes or exogenous DNA damaging agents and can promote chromosomal rearrangements, including translocations, deletions, or chromosome loss. In mammalian cells, both homologous recombination and nonhomologous end joining (NHEJ) are important DSB repair pathways for the maintenance of genomic stability. Using a mouse embryonic stem cell system, we previously demonstrated that a DSB in one chromosome can be repaired by recombination with a homologous sequence on a heterologous chromosome, without any evidence of genome rearrangements (C. Richardson, M. E. Moynahan, and M. Jasin, Genes Dev., 12:3831-3842, 1998). To determine if genomic integrity would be compromised if homology were constrained, we have now examined interchromosomal recombination between truncated but overlapping gene sequences. Despite these constraints, recombinants were readily recovered when a DSB was introduced into one of the sequences. The overwhelming majority of recombinants showed no evidence of chromosomal rearrangements. Instead, events were initiated by homologous invasion of one chromosome end and completed by NHEJ to the other chromosome end, which remained highly preserved throughout the process. Thus, genomic integrity was maintained by a coupling of homologous and nonhomologous repair pathways. Interestingly, the recombination frequency, although not the structure of the recombinant repair products, was sensitive to the relative orientation of the gene sequences on the interacting chromosomes.

* Corresponding author. Mailing address: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, and Cornell University Graduate School of Medical Sciences, 1275 York Ave., New York, NY 10021. Phone: (212) 639-7438. Fax: (212) 717-3317. E-mail: m-jasin{at}ski.mskcc.org.

Molecular and Cellular Biology, December 2000, p. 9068-9075, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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