UV-induced binding of ING1 to PCNA regulates the induction of apoptosis.
Previous studies have shown that UV-induced binding of p21(WAF1) to PCNA through the PCNA-interacting protein (PIP) domain in p21(WAF1) promotes a switch from DNA replication to DNA repair by altering the PCNA protein complex. Here we show that the p33(ING1b) isoform of the ING1 candidate tumour suppressor contains a PIP domain. UV rapidly induces p33(ING1b) 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 p33(ING1b) 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 p21(WAF1), but not by p16(MTS1), which has no PIP sequence. In contrast to wild-type p33(ING1b), 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-p33(ING1b) 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.
Scott
M
M
Department of Biochemistry, Faculty of Medicine, The University of Calgary, 3330 Hospital Drive, NW, Calgary, Alberta T2N 4N1, Canada.
Bonnefin
P
P
Vieyra
D
D
Boisvert
F M
FM
Young
D
D
Bazett-Jones
D P
DP
Riabowol
K
K
D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites / Q000502:physiology; D018797:Cell Cycle Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology; D004261:DNA Replication / Q000502:physiology; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000166:cytology; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology / Q000528:radiation effects; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012326:RNA Splicing; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; D025521:Tumor Suppressor Proteins