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A Nuclear Protein Complex Containing High Mobility Group Proteins B1 and B2, Heat Shock Cognate Protein 70, ERp60, and Glyceraldehyde-3-Phosphate Dehydrogenase Is Involved in the Cytotoxic Response to DNA Modified by Incorporation of Anticancer Nucleoside Analogues¹

Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 [E. Y. K., N. F. K., W. E. E.]; University of Tennessee, Memphis, Tennessee 38163 [E. Y. K., N. F. K., W. E. E.]; and San Raffaele Scientific Insitute, via Olgettina 58, 20132 Milano, Italy [M. E. B.]

Thiopurine treatment of human leukemia cells deficient in components of the mismatch repair system (Nalm6) initiated apoptosis after incorporation into DNA, as revealed by caspase activation and terminal deoxynucleotidyl transferase-mediated nick end labeling assay. To elucidate the cellular sensor(s) responsible for recognition of DNA damage in cells with an inactive mismatch repair system, we isolated a multiprotein nuclear complex that preferentially binds DNA with thioguanine incorporated. The components of this nuclear multiprotein complex, as identified by protein mass spectroscopy, included high mobility group proteins 1 and 2 (HMGB1, HMGB2), heat shock protein HSC70, protein disulfide isomerase ERp60, and glyceraldehyde 3-phosphate dehydrogenase. The same complex was also shown to bind synthetic oligodeoxyribonucleotide duplexes containing the nonnatural nucleosides 1-ß-D-arabinofuranosylcytosine or 5-fluoro-2'-deoxyuridine. Fibroblast cell line derived from Hmgb1^-/- murine embryos had decreased sensitivity to thiopurines, with an IC₅₀ 10-fold greater than Hmgb1-proficient cells (P < 0.0001) and exhibited comparable sensitivity to vincristine, a cytotoxic drug that is not incorporated into DNA. These findings indicate that the HMGB1-HMGB2-HSC70-ERp60-glyceraldehyde 3-phosphate dehydrogenase complex detects changes in DNA structure caused by incorporation of nonnatural nucleosides and is a determinant of cell sensitivity to such DNA modifying chemotherapy.

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