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J. Biol. Chem., Vol. 279, Issue 35, 36462-36469, August 27, 2004

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DNA Repair Defects Channel Interstrand DNA Cross-links into Alternate Recombinational and Error-prone Repair Pathways^*

Wilma A. Saffran, Shaila Ahmed, Sherly Bellevue, Gillian Pereira, Teleka Patrick, Wendy Sanchez, Sandra Thomas, Marie Alberti¶, and John E. Hearst¶

From the Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, New York 11367 and ^¶Department of Chemistry, University of California and Lawrence Berkeley National Laboratory, Berkeley, California 94720

The repair of psoralen interstrand cross-links in the yeast Saccharomyces cerevisiae involves the DNA repair groups nucleotide excision repair (NER), homologous recombination (HR), and post-replication repair (PRR). In repair-proficient yeast cells cross-links induce double-strand breaks, in an NER-dependent process; the double-strand breaks are then repaired by HR. An alternate error-prone repair pathway generates mutations at cross-link sites. We have characterized the repair of plasmid molecules carrying a single psoralen cross-link, psoralen monoadduct, or double-strand break in yeast cells with deficiencies in NER, HR, or PRR genes, measuring the repair efficiencies and the levels of gene conversions, crossing over, and mutations. Strains with deficiencies in the NER genes RAD1, RAD3, RAD4, and RAD10 had low levels of cross-link-induced recombination but higher mutation frequencies than repair-proficient cells. Deletion of the HR genes RAD51, RAD52, RAD54, RAD55, and RAD57 also decreased induced recombination and increased mutation frequencies above those of NER-deficient yeast. Strains lacking the PRR genes RAD5, RAD6, and RAD18 did not have any cross-link-induced mutations but showed increased levels of recombination; rad5 and rad6 cells also had altered patterns of cross-link-induced gene conversion in comparison with repair-proficient yeast. Our observations suggest that psoralen cross-links can be repaired by three pathways: an error-free recombinational pathway requiring NER and HR and two PRR-dependent errorprone pathways, one NER-dependent and one NER-independent.

Received for publication, March 1, 2004 , and in revised form, June 4, 2004.

^* This work was supported in part by grants from the City University of New York PSC-CUNY research award program (to W. A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Queens College, City University of New York, Dept. of Chemistry and Biochemistry, 65-30 Kissena Blvd., Flushing, NY 11367. Tel.: 718-997-4195; Fax: 718-997-5531; E-mail: Wilma_Saffran{at}qc.edu.

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