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The Tumor Suppressor Candidate p33^ING1 Mediates Repair of UV-Damaged DNA¹

Division of Dermatology, Department of Medicine, University of British Columbia, and Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia V6H 3Z6, Canada [K-J. C., P. L., G. L.], and Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Smithville, Texas 78957 [D. M.]

	ABSTRACT

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The biological functions of the tumor suppressor, ING1, have been studied extensively in the last 5 years since it was cloned. It shares many biological functions with those of p53 and has been reported to mediate growth arrest, senescence, apoptosis, anchorage-dependent growth, and chemosensitivity. Some of these functions, such as cell cycle arrest and apoptosis, have been shown to be dependent on the activity of both ING1 and p53 proteins. In this study, we report that p33^ING1 (one of ING1 isoforms) is also involved in the modulation of DNA repair. We found that overexpression of p33^ING1 enhances repair of UV-damaged DNA and that p53 is required for the repair process. Furthermore, binding between ING1 and GADD45 has been detected. These observations suggest that p33^ING1 cooperates with p53 in nucleotide excision repair and that GADD45 may be one of its components.

	Introduction

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The tumor suppressor gene ING1 has been shown to inhibit cell growth in the G₁ phase by transactivating the cyclin-dependent kinase inhibitor p21^waf1 in the presence of p53 (1 , 2) . Overexpression of ING1 enhances serum starvation-induced cell death (3) , and adenovirus-mediated transfer of both ING1 and p53 induces apoptosis in glioma cells (4) . ING1 can also sensitize cells to stress agents, such as etoposide and -irradiation, in wild-type but not in p53-deficient cell lines (2) . Furthermore, ING1 appears to play a role in senescence, because senescent cells express higher levels of ING1, and antisense ING1 can increase the replicative life of the cell (5) . Higher expression and rearrangement of ING1 have been reported in neuroblastoma cell lines (1) . Decreased expression of ING1 was seen in lymphoid tumor cell lines (6) , breast cancer primaries and cell lines (7 , 8) , and gastric cancers (9) . A few missense and silent mutations in ING1 were also detected in head and neck squamous cell carcinomas (10) . Findings from these studies strongly support the notion that ING1 is a tumor suppressor gene and plays a significant role in the process of carcinogenesis. Four isoforms of the ING1 gene, encoding M_r 46,751, 31,843, 27,000, and 23,656 proteins, have thus far been found (10, 11, 12) . Their biological functions are being investigated intensively.

In light of the functional similarities between ING1 and p53 and the recent finding that the expression of the p33^ING1 isoform is induced by UV irradiation in a dose-/time-dependent and tissue-specific manner (13) , we investigated if p33^ING1 plays a role in UV-stress response, such as repair of UV-damaged DNA. In this study, we show that overexpression of p33^ING₁ confers enhanced repair efficiency of UV-damaged DNA in melanoma cells and that this repair capability of p33^ING1 requires the participation of p53.

	Materials and Methods

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Cell Lines and Culture.
MMRU and HeLa cells were maintained in DMEM supplemented with 10% fetal bovine serum and HCT116-/- cells in McCoy’s 5A medium with 10% fetal bovine serum (Canadian Life Technologies, Inc., Mississauga, Ontario, Canada) at 37°C in a 5% CO₂ atmosphere. The p53 mutational status of MMRU has been determined previously (14) .

UV Irradiation.
Medium was removed, and the cells were exposed to UVB (290–320 nm) using a bank of four unfiltered FS40 sunlamps (Westinghouse, Bloomfield, NJ). Medium was replaced, and cells were incubated in a 5% CO₂ incubator at 37°C after UVB irradiation.

Western Analysis.
Cells were harvested by scraping and solubilized by the triple detergent lysis buffer containing 50 mM Tris-Cl (pH 8.0), 150 mM NaCl, 0.02% sodium azide, 0.1% SDS, 1% NP40, 100 µg/ml phenylmethylsulfonyl fluoride, 1 µg/ml aprotinin, 1 µg/ml leupeptin, and 1 µg/ml pepstatin A. Concentrations of proteins were determined by the DC Protein Assay (Bio-Rad, Mississauga, Ontario, Canada). Fifty µg/lane of proteins were separated on 10% polyacrylamide/SDS gels and electroblotted onto polyvinylidene difluoride filters. Filters were incubated with primary antisera for 1 h, followed with 3x washes in PBS for 5 min, and then were incubated with horseradish peroxidase-conjugated secondary antisera for 1 h at room temperature. Signals were detected with SuperSignal enhanced chemiluminescence (Pierce, Rockford, IL). Antibodies used for Western blotting were anti-p33^ING1 rabbit polyclonal antibody (PharMingen, Mississauga, Ontario, Canada), anti-p53 DO-1 mouse monoclonal, anti-GADD45 mouse monoclonal, anti-XPA rabbit polyclonal, and anti-XPB rabbit polyclonal antibodies (Santa Cruz Biotechnology, Santa Cruz, CA), secondary IgG (Calbiochem, San Diego, CA), and anti-ß-actin goat monoclonal antibody (Santa Cruz Biotechnology).

Northern Analysis.
Total RNA was extracted by TriZol reagent, and the concentrations were determined by UV spectrophotometry. Samples were heated to 65°C and run on 1% agarose gels containing formaldehyde and 0.5 µg/ml ethidium bromide. After separation, capillary transfer to nitrocellulose was performed overnight at room temperature, and its efficiency was assessed by UV light. The blot was then baked for 2 h in a vacuum oven at 80°C. Prehybridization was carried out by incubating the blot with a mixture containing 6 x saline-sodium phosphate-EDTA, 5 x Denhardt’s reagent, 0.5% SDS, and 100 µg/ml yeast tRNA for 1 h at 65°C. Hybridization was done by incubating the blot with the labeled probe at 65°C for 16–24 h. Filters were washed with 2 x SSC/0.1% SDS once for 15 min at room temperature and three washes 20 min each at 65°C. Blots were visualized on X-ray films after an overnight exposure.

Transfection.
Cells were grown to 50–60% confluency. The ratio of 1 µg of DNA:25 µl of Effectene reagent (Qiagen, Mississauga, Ontario, Canada) was used for transfection. Plasmids used for transfection included pCI-p33^ING1B and pCI-antisense-p33^ING1B (a kind gift from Dr. Karl Riabowol, University of Calgary, Calgary, Alberta, Canada), pED1 and pECH (a kind gift from Dr. Samuel Benchimol, Univ. of Toronto, Toronto, Ontario, Canada), and pCMVcat (a kind gift from Dr. Lawrence Grossman, Johns Hopkins University, Baltimore, MD).

Host-Cell-Reactivation Assay.
The pCMVcat plasmid contains a gene encoding for cat, under the transcriptional control of the immediate early promoter of the human cytomegalovirus. The pCMVcat plasmid DNA was irradiated at 40, 80, and 480 mJ/cm² using an UV-cross-linker at 50 µg/ml final concentration and used for transfection. Forty h after transfection, cells were harvested, and the cell pellet was resuspended in a 50-µl solution of 0.25 M Tris-Cl (pH 8.0) and 5 mM EDTA. Cell-free extracts of the transfected cells were made by three repeated freeze-thawings (liquid nitrogen to freeze; 37°C to thaw), heated to 65°C for 10 min, and centrifuged at 12,000 x g for 10 min, and the cleared supernatant was used for the CAT assay. The assay reaction mixture contained 7.5 µl of 5 mM chloramphenicol, 50 µl of cell-free extract, 1 µl of 2.5 mM [³H]acetyl-CoA, and 16.5 µl of distilled water. The reaction mixture was incubated at 37°C for 90 min. After incubation, 200 µl of ice-cold ethyl acetate was added, and tubes were shaken and centrifuged at 12,000 x g for 5 min. After quick-freezing the aqueous phase in a dry ice/ethanol bath, the organic phase was removed and extracted with 200 µl of distilled water. The organic phase was dried to completion, and radioactivity was determined in a scintillation counter. Determinants were performed in triplicates. Controls included transfection with undamaged plasmid DNA and mock transfection without plasmid DNA.

RIA.
Antisera were raised against DNA dissolved in 10% acetone and irradiated with UVB light under conditions that have been shown to produce CPDs³ exclusively. Heat-denatured sample DNA (2–5 µg) was incubated with 5–10 pg of poly(deoxyadenylated TMP; labeled to >5 x 10⁸ cpm/µg by nick translation with [³²P] dideoxythymidine 5'-triphosphate) in a total volume of 1 ml of 10 mM Tris (pH 7.8), 150 mM NaCl, 1 mM EDTA, and 0.15% gelatin (Sigma Chemical Co., St. Louis, MO). Antiserum was added at a dilution that yielded 30–60% binding to labeled ligand, and, after incubation overnight at 4°C, the immune complex was precipitated with goat antirabbit immunoglobulin (Calbiochem) and carrier serum from nonimmunized rabbits (UTMDACC; Science Park/Veterinary Division, Bastrop, TX). After centrifugation, the pellet was dissolved in tissue solubilizer (NCS; Amersham, Piscataway, NJ) and mixed with ScintiSafe (Fisher, Hampton, NH) containing 0.1% glacial acetic acid, and the ³²P was quantified by liquid scintillation spectrometry. Under these conditions, antibody binding to an unlabeled competitor inhibits antibody binding to the radiolabeled ligand. Sample inhibition is extrapolated through a standard (dose-response) curve to determine the number of photoproducts in 10⁶ bases (i.e., CPDs/mb). For the standard, we used double-stranded salmon testis DNA (Sigma Chemical Co.) irradiated with increasing doses of UVC light, heat-denatured, aliquoted, and kept frozen at -20°C. Rates of photoproduct induction were quantified using nonimmunological enzymatic and biochemical techniques and determined to be 0.81 CPDs/mb/mJ/cm².

Immunoprecipitation.
Cells were grown to 80% confluency in 100-mm tissue culture dishes. Their lysates were harvested and incubated with anti-p33^ING1 antibody or a nonspecific control anti-interleukin-12B rabbit polyclonal antibody (Santa Cruz Biotechnology) at 4°C for 1 h and then with protein A-Sepharose at 4°C overnight. The beads were washed three times with solubilization buffer before boiling for 5 min. The precipitates were then resolved by electrophoresis, followed by Western analysis as described above.

	Results

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UV Induces p33^ING1 Expression in a Dose- and Time-dependent Manner.
We first examined whether p33^ING1 would respond to UV in a human melanoma cell line, MMRU, which contains wild-type p53 (14) . We found that there was a clear induction of p33^ING1 protein with increasing UV doses (Fig. 1, A and B) . To test the possibility that the induction was attributable to transcriptional regulation, we examined the RNA levels at various time points after UV irradiation. We found that UV-induced p33^ING1 was indeed a result of transcriptional control (Fig. 1C) . These results indicate that p33^ING1 was induced in a dose- and time-dependent manner after UV irradiation.

View larger version (36K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. p33ING1 is UV-inducible in a dose- and time-dependent manner. A, Western analysis of UV-induced p33ING1 protein expression in MMRU cells. Cells were UV-irradiated at 0, 10, 20, 40, and 80 mJ/cm2 and harvested after 24-h incubation. An anti-p33ING1 antibody was used for primary antibody incubation, and ß-actin was used as loading control. Lane C, lysate from MMRU cells overexpressing the pCI-p33ING1B plasmid, confirming that the bands induced by UV irradiation were the p33ING1 protein. B, densitometry of p33ING1 induction in A. C, Northern analysis of UV-induced p33ING1 mRNA in MMRU cells. Cells were UV-irradiated at 40 mJ/cm2 and harvested at 0-, 2-, 4-, 8-, 12-, and 24-h time points. The p33ING1 probe was first made by amplifying a 577-bp fragment by PCR using primer 1 (5'-GATCCTGAAGGAGCTAGACG-3') and primer 2 (5'-AGAAGTGGAACCACTCGATG-3') and then labeling it with [-32P]dCTP (10 mCi/ml) according to the manufactured protocol in the Random Primers DNA Labeling System (Canadian Life Technologies, Inc.). 18s rRNA was used as loading control.

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. p33ING1 enhances UV-damaged DNA repair. A, effect of p33ING1 on repair of UV-damaged plasmid DNA by host-cell-reactivation assay. Undamaged or UV-damaged pCMVcat plasmids were cotransfected with vector, pCI-p33ING1, or pCI-antisense p33ING1 into MMRU cells and incubated at 37°C with 5% CO2 for 40 h. CAT activity was determined by scintillation counting and expressed as: net dpm damage dose/net dpm zero dose. Experiments were performed in triplicates. Shown are representatives of two independent sets of experiments. B, effect of p33ING1 on repair of UV-damaged genomic DNA by RIA. MMRU cells transfected with vector or p33ING1 plasmids were UV-irradiated at 20 mJ/cm2, and genomic DNA was harvested at 0, 4, 24, and 48 h. The percentage of remaining CPDs was then measured using antisera specific for CPDs (data presented as average of two independent experiments).

View larger version (35K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. p33ING1-mediated DNA repair is p53-dependent. A, Western analysis of p53 protein expression in UV-irradiated MMRU cells. Cells were UV-irradiated at 0, 10, 20, 40, and 80 mJ/cm2 and harvested after 24-h incubation. An anti-p53 antibody was used for primary antibody incubation, and ß-actin was used as loading control. B, Western analysis of p53 and p33ING1 proteins in MMRU cells transfected with the dominant-negative mutant-p53 (pED1) expression vector. C, effect of p53 on p33ING1-mediated DNA repair. Host-cell-reactivation assay was performed on MMRU cells transfected with UV-damaged (40 mJ/cm2) pCMVcat plasmid and control vector, p33ING1, pED1, p33ING1/pED1, pECH, or p33ING1/pECH. Forty h later, CAT activity was measured using the undamaged pCMVcat as control. Experiments were performed in triplicates. Shown is a representative of two independent sets of experiments.

View larger version (42K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. ING1 physically interacts with GADD45 but does not transcriptionally up-regulate GADD45, XPA, or XPB. A, effect of p33ING1 on the expression of GADD45, XPA, and XPB proteins. MMRU cells were transfected with vector alone, p33ING1, or antisense p33ING1 expression vectors. Twenty-four h after transfection, cells were harvested, and their lysates were analyzed by Western blotting using anti-GADD45, anti-XPA, and anti-XPB antibodies. ß-actin served as a loading control. B, coimmunoprecipitation of ING1 with XPA, XPB, and GADD45. MMRU total cell lysates were immunoprecipitated with a nonspecific control antibody (Lane 1), with the anti-ING1 antibody that recognizes different isoforms of ING1 (Lane 2), or without any antibody (Lane 3). Antibodies against XPA, XPB, and GADD45 were then used in Western analysis. The physical binding between ING1 and GADD45 was observed in three separate experiments.

	Discussion

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For the first time, we demonstrate that overexpression of p33^ING1 enhances nucleotide excision repair of both UV-damaged genomic DNA and exogenous plasmid DNA (Fig. 2) , further supporting the notion that p33^ING1 is a tumor suppressor. Nucleotide excision repair is a crucial stress-response mechanism to maintain the genomic stability. UV radiation damages DNA primarily in the forms of CPDs and photoproducts (6, 5, 4) . These photoproducts are repaired by nucleotide excision repair, which involves a complex series of proteins that orchestrate the identification and removal of damaged DNA, addition of nucleotides, and, finally, religation of the DNA strand (21) . If UV-induced DNA photoproducts are not promptly removed, they will in turn lead to mutation and skin carcinogenesis; e.g., xeroderma pigmentosum patients who have defects in nucleotide excision repair suffer a 1000-fold increase in skin cancer incidence (22) .

Wild-type p53 binds to and modulates XPB and XPD (23) , two components of the TFIIH transcription unit that possesses helicase, ATPase, and kinase activity (24) . However, our results demonstrate that p33^ING1 does not transcriptionally regulate or physically bind to XPA and XPB (Fig. 4) . The physical association between p33^ING1 and GADD45 (Fig. 4B) suggests that p33^ING1 may be a crucial component in the GADD45-mediated nucleotide excision repair pathway. The fact that GADD45 is up-regulated by p53 and that p33^ING1 requires the participation of functional p53 in DNA repair (Fig. 3) further supports the close association of p33^ING1 and GADD45. Increasing evidence has indicated that GADD45 is essential in UV-damaged DNA repair and genome stability (17 , 25 , 26) . Recently (27) , an interesting report shows that GADD45 can recognize UV-altered chromatin state and modulate DNA accessibility to repair proteins such as DNase I and T4 endonuclease V. It would be of interest to exploit the mechanistic role of p33^ING1 in this GADD45-mediated repair process.

Taken together, our results strongly demonstrate that p33^ING1 enhances the nucleotide excision repair of UV-damaged DNA. Because there is a strong causal relationship between UV exposure and melanoma formation, loss or inactivation of p33^ING1 can potentially contribute to neoplastic development.

	ACKNOWLEDGMENTS

 
We thank K. Riabowol for the pCI-p33^ING1B and pCI-antisense-p33^ING1B plasmids, S. Benchimol for the pED1 and pECH plasmids, and L. Grossman for the pCMVcat plasmid. We thank R. Byers for the MMRU, S. Dedhar for HeLa, and B. Vogelstein for HCT116-/- cell lines. We thank Payman Hojabrpour for technical assistance in immunoprecipitation.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by grants from the Canadian Institutes of Health Research and scientist awards from Vancouver Hospital and Health Sciences Center (to G. L.).

² To whom requests for reprints should be addressed, at Jack Bell Research Center, 2660 Oak Street, Vancouver, BC, V6H 3Z6 Canada. Phone: (604) 875-5826; Fax: (604) 875-4497; E-mail: gangli{at}interchange.ubc.ca

³ The abbreviations used are: CPD, cyclobutane pyrimidine dimer; CAT, chloramphenicol acetyltransferase.

Received 2/13/01. Accepted 5/11/01.

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