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Originally published In Press as doi:10.1074/jbc.M101208200 on May 8, 2001

J. Biol. Chem., Vol. 276, Issue 28, 25736-25741, July 13, 2001
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Interaction of FACT, SSRP1, and the High Mobility Group (HMG) Domain of SSRP1 with DNA Damaged by the Anticancer Drug Cisplatin*

Amanda T. YarnellDagger §, Sangtaek Oh, Danny Reinberg, and Stephen J. LippardDagger ||

From the Dagger  Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 and the  Howard Hughes Medical Institute, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Division of Nucleic Acids Enzymology, Department of Biochemistry, Piscataway, New Jersey 08854-5635

The structure-specific recognition protein SSRP1, initially isolated from expression screening of a human B-cell cDNA library for proteins that bind to cisplatin (cis-diamminedichloroplatinum(II))-modified DNA, contains a single DNA-binding high mobility group (HMG) domain. Human SSRP1 purifies as a heterodimer of SSRP1 and Spt16 (FACT) that alleviates the nucleosomal block to transcription elongation by RNAPII in vitro. The affinity and specificity of FACT, SSRP1, and the isolated HMG domain of SSRP1 for cisplatin-damaged DNA were investigated by gel mobility shift assays. FACT exhibits both affinity and specificity for DNA damaged globally with cisplatin compared with unmodified DNA or DNA damaged globally with the clinically ineffective trans-DDP isomer. FACT binds the major 1,2-d(GpG) intrastrand cisplatin adduct, but its isolated SSRP1 subunit fails to form discrete, high affinity complexes with cisplatin-modified DNA under similar conditions. These results suggest that Spt16 primes SSRP1 for cisplatin-damaged DNA recognition by unveiling its HMG domain. As expected, the isolated HMG domain of SSRP1 is sufficient for specific binding to cisplatin-damaged DNA and binds the major cisplatin 1,2-d(GpG) intrastrand cross-link. The affinity and specificity of FACT for cisplatin-modified DNA, as well as its importance for transcription of chromatin, suggests that the interaction of FACT and cisplatin-damaged DNA may be crucial to the anticancer mechanism of cisplatin.

* This work was supported by NCI National Institutes of Health Grant CA34992 (to S. J. L.) and by grants from the National Institutes of Health and Howard Hughes Medical Institute (to D. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ National Science Foundation Predoctoral Fellow.

|| To whom correspondence should be addressed: Dept. of Chemistry, Massachusetts Institute of Technology, Rm. 18-590, Cambridge, MA 02139. Tel.: 617-253-1892; Fax: 617-258-8150; E-mail: lippard@lippard.mit.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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