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Deficiency in DNA Polymerase ß Provokes Replication-dependent Apoptosis via DNA Breakage, Bcl-2 Decline and Caspase-3/9 Activation¹

Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany

Cells deficient in DNA polymerase ß (ß-pol) are impaired in base excision repair (BER) and hypersensitive to various DNA damaging agents, including methylating mutagens. Hypersensitivity of ß-pol-deficient cells to methylating agents is because of induction of apoptosis (Ochs et al., Cancer Res., 59: 1544–1551, 1999), indicating incompletely repaired DNA damage to trigger the response. Here we show that defective BER in ß-pol-null cells results in an early and transient increase in the frequency of DNA single-strand breaks on treatment with methyl methanesulfonate. These breaks arising as repair intermediates are not likely to trigger apoptosis directly because they were repaired efficiently and generated both in resting and proliferating cells, whereas only proliferating cells underwent with high frequency apoptosis after methylation. Therefore, we propose that single-strand breaks are converted into another kind of critical apoptosis-triggering lesion during replication. These critical secondary DNA lesions are likely to be nonrepaired DNA double-strand breaks (DSBs), which are formed at higher frequency in ß-pol-null than in wild-type cells. Apoptosis was a late response not detectable before 24 h after methylation and was preceded by DSBs formation, extensive chromosomal breakage, and decline in Bcl-2 level and caspase-9 and caspase-3 activation. Caspase-8 was not significantly activated. Transfection of ß-pol-null cells with bcl-2 protected against methylation-induced apoptosis, indicating Bcl-2 to be causally involved. Overall, the data demonstrate that in cells lacking ß-pol, defective BER results in incompletely repaired DNA damage, which triggers apoptosis in a replication-dependent way by activating the mitochondrial death pathway. It is suggested that DSBs act as a critical ultimate apoptosis-inducing lesion.

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