DNA Replication Arrest and P53-Dependent and P53-Independent Cell Death Pathways in Xeroderma Pigmentosum Variant Cells.

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INTRODUCTION. Xeroderma pigmentosum variant (XPV) cells lack the low-fidelity DNA polymerase, pol η, and as a result cannot replicate UV damaged DNA and experience prolonged arrest in the S phase (1, 2). Primary XPV fibroblasts and XPV fibroblasts transformed by HPV16(E6/E7) do not show early UV-induced apoptosis, but remain arrested for up to 48 hr without evidence of cell death (3). XPV cells transformed by SV40, however, show very early apoptosis, which is further enhanced by caffeine, and a large fraction of the cell population detaches from the substrate within 10-20 hr (3, 4). In the presence of caffeine, apoptosis is detectable in 1-2 hr. Transfection of SV40 transformed cells with the XPV gene, hRad30A, on a CMV promoter suppressed UV-induced apoptosis. Normal cells show parallel apoptotic behavior, but at a lower level. Paradoxically, when cells are assayed for colony formation after UV irradiation, the XPV cells transformed by HPV16,E6/E7) are much more sensitive than SV40 transformed or primary cells (3). Therefore the degree of apoptosis is no measure of long-term survival, and a non-apoptotic pathway of cell death, caused by DNA replication arrest, is associated with higher lethality than the apoptotic pathway.