UV-induced binding of ING1 to PCNA regulates the induction of apoptosis

Abstract

Previous studies have shown that UV-induced binding of p21WAF1 to PCNA through the PCNA-interacting protein (PIP) domain in p21WAF1 promotes a switch from DNA replication to DNA repair by altering the PCNA protein complex. Here we show that the p33ING1b isoform of the ING1 candidate tumour suppressor contains a PIP domain. UV rapidly induces p33ING1b to bind PCNA competitively through this domain, a motif also found in DNA ligase, the DNA repair-associated FEN1 and XPG exo/endonucleases, and DNA methyltransferase. Interaction of p33ING1b with PCNA occurs between a significant proportion of ING1 and PCNA, increases more than tenfold in response to UV and is specifically inhibited by overexpression of p21WAF1, but not by p16MTS1, which has no PIP sequence. In contrast to wild-type p33ING1b, ING1 PIP mutants that do not bind PCNA do not induce apoptosis, but protect cells from UV-induced apoptosis, suggesting a role for this PCNA-p33ING1b interaction in eliminating UV-damaged cells through programmed cell death. These data indicate that ING1 competitively binds PCNA through a site used by growth regulatory and DNA damage proteins, and may contribute to regulating the switch from DNA replication to DNA repair by altering the composition of the PCNA protein complex.