Alterations of NAD and adenylyl dinucleotide metabolism in Chediak-Higashi syndrome fibroblasts.

Chediak-Higashi syndrome (CHS) cells have been previously observed to exhibit several of the same characteristics as those of xeroderma pigmentosum (XP) and xeroderma pigmentosum variants. Cultured CHS fibroblasts have been examined for altered responses in both depletion of NAD and elevation of diadenosine-5',5"'-tetraphosphate (Ap4A) following DNA damage since both responses have been reported as altered in XP cells and since Ap4A has been reported as absent from the platelets of CHS patients. Lowering of NAD following UV irradiation occurred in CHS cells in a manner similar to that of control and XP variant cells, but different from that of XP cells. CHS fibroblasts were not found to be deficient in Ap4A and exhibit basal levels very similar to those of control fibroblasts. No change in Ap4A pools were observed which correlated with cell growth, in contrast to previously published reports. Furthermore, while Ap4A levels are not elevated in XP cells, we observe an elevation of Ap4A pools in CHS cells which mimics the elevations observed in control and XP variant cells. We conclude that: (1) CHS cells more closely resemble control or XP variant cells than XP cells with regard to NAD lowering and Ap4A elevation following UV irradiation; (2) the photosensitivity exhibited by CHS cells is not due to general defects in the synthesis of poly(ADP-ribose) from NAD or in Ap4A metabolism; and (3) alteration of Ap4A pool size in CHS fibroblasts is inappropriate as a biochemical marker for CHS.