Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium Susan G. Komen for the Cure-AACR Outstanding Investigator Award for Breast Cancer Research
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
Cancer Research 66, 11594-11599, December 15, 2006. doi: 10.1158/0008-5472.CAN-06-4138
© 2006 American Association for Cancer Research
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by White, D. E.
Right arrow Articles by Rauscher, F. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by White, D. E.
Right arrow Articles by Rauscher, F. J., III

Priority Reports

KAP1, a Novel Substrate for PIKK Family Members, Colocalizes with Numerous Damage Response Factors at DNA Lesions

David E. White, Dmitri Negorev, Hongzhuang Peng, Alexey V. Ivanov, Gerd G. Maul and Frank J. Rauscher, III

The Wistar Institute, Philadelphia, Pennsylvania

Requests for reprints: Frank J. Rauscher III, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Phone: 215-898-0995; Fax: 215-898-3929; E-mail: rauscher{at}wistar.org.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The DNA damage response requires a coordinated nucleo-cytoplasmic cascade of events, which ultimately converge on damaged DNA packaged in chromatin. Few connections between the proteins that remodel chromatin and the proteins that mediate this damage response have been shown. We have investigated the DNA damage–induced phosphorylation of the KRAB-ZFP–associated protein 1 (KAP1), the dedicated corepressor for Krüppel-associated box (KRAB) zinc finger protein (ZFP) proteins. We show that KAP1 is rapidly phosphorylated following DNA damage by members of the phosphatidylinositol-3 kinase–like family of kinases. This phosphorylation occurs at a single amino acid residue that is conserved from mice to humans and is located adjacent to the bromodomain, suggesting that it may regulate chromatin recognition by that module. Phosphorylated KAP1 rapidly localizes to sites of DNA strand breaks in the nucleus in response to ionizing radiation. This discovery provides a novel link between chromatin-mediated transcriptional repression and the recognition/repair of DNA, which must be accomplished by the cellular DNA damage response. (Cancer Res 2006; 66(24): 11594-9)


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Of the three nuclear phosphatidylinositol-3 kinase–like (PIKK) family members, ataxia-telangiectasia mutated (ATM), ATM and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PK), ATM has been shown to drive the DNA damage pathways initiated by ionizing radiation. In fact, ataxia telangiectasia was one of the first diseases linking radiosensitivity to a lack of a damage responsive protein, in this case ATM (1). Further studies have revealed that ATM is a key DNA damage responsive kinase required for the homologous recombination double-stranded break repair pathway (2). Following irradiation, ATM kinase phosphorylates numerous proteins involved in DNA repair, including H2AX, topoisomerase II binding protein 1 (TopBP1), p53 binding protein 1 (53BP1), and breast cancer 1 early onset (BRCA1; refs. 3–6), as well as itself. Similar to the damage response proteins it phosphorylates (3–6), ATM has been shown to aggregate and form distinct foci at sites of double-stranded breaks (7). DNA-PK also responds to double-stranded breaks but plays a role in the nonhomologous end joining DNA repair pathway. Because the nonhomologous end joining pathway utilizes nonhomologous regions of DNA to mediate the double-stranded break repair, mutations and deletions often result. Conversely, no errors occur during homologous recombination repair because the sister chromatid is utilized as a template for repair. Both homologous recombination and nonhomologous end joining DNA repair pathways occur simultaneously in damaged cells and are both critical for recovery (8). Evidence for this has been obtained in DNA-PK null cells that, like ATM null cell lines, exhibit radiosensitivity (9). Although some studies have shown ATR to be activated in response to ionizing radiation, ATR responds primarily to the presence of ssDNA lesions, UV-induced DNA damage, and stalled replication forks (10).

The Krüppel-associated box zinc finger protein (KRAB-ZFP) silencing complex is one of the best-characterized systems of gene repression and silencing. KRAB-ZFPs mediate repression through an association with KRAB-ZFP–associated protein 1 (KAP1; ref. 11). KAP1, a member of the transcription intermediary factor (TIF1) family of transcriptional regulators, acts as a molecular scaffold, connecting KRAB-ZFPs, which bind site-specifically to DNA to the repression machinery that targets neighboring chromatin. The RING finger-B box-coiled-coil domain of KAP1 associates with the KRAB domain of KRAB-ZFPs (12). KAP1 recruits heterochromatin protein 1 (HP1) to histones through a PxVxL motif in its centrally located HP1 binding domain (13). Additionally, KAP1 associates with the histone methyltransferase SETDB1 and the member of the NuRD/Mi2 histone deacetylase complex Mi2-{alpha} via its COOH-terminal plant homeodomain and bromodomain, respectively (14, 15). KAP1 assembles these proteins onto KRAB-ZFPs to coordinate the deacetylation and methylation of histones, as well as the deposition of HP1, all of which cooperatively result in heritable gene silencing through the formation of heterochromatin (11).

Although the role of KAP1 in repression has been elucidated, it is not known what role, if any, the components of the silencing machinery play in the DNA damage response. In this study, we generated a new phosphospecific antibody to examine the phosphorylation of KAP1 at Ser824 in response to both ionizing radiation and the radiomimetic agent neocarzinostatin. We determined that the phosphorylation of KAP1 at this site is mediated by ATM, ATR, and DNA-PK. Moreover, KAP1 phosphorylation is an early event and, like other factors critical to the DNA damage response, phosphorylated KAP1 rapidly localizes to DNA lesions.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell culture. U2OS and FF2425 cells (both generous gifts from T. Halazonetis, Department of Molecular Biology, University of Geneva, Geneva, Switzerland) were grown in DMEM. AT5BIVA cells (Coriell Cell Repositories) were grown in MEM containing 2x concentrations of vitamin solution and both essential and nonessential amino acids (Invitrogen). MO59J and MO59K cells (American Type Culture Collection) were grown in a 50:50 solution of DMEM and Ham's F12 containing 0.05 mmol/L nonessential amino acids (Invitrogen), 2.5 mmol/L L-glutamine, 0.5 mmol/L sodium pyruvate, and 15 mmol/L HEPES. All media were supplemented with 10% fetal bovine serum and penicillin-streptomycin. Cells were incubated at 5% CO2, 37°C.

Protein extract preparation. Nuclear extracts were prepared as described in ref. (16) with 1% Phosphatase Inhibitor Cocktail 1 (Sigma) added to the lysis buffers.

Generation of phosphospecific KAP1 antibody. Antibody-containing serum was affinity purified over two columns, one containing an unmodified KAP1 peptide followed by another containing the KAP1 phosphopeptide. The phosphospecific KAP1 antibody used in this study was then eluted from the second column (Open Biosystems).

Western blotting. Proteins electrotransferred from Tris-glycine gels onto polyvinylidene difluoride membranes (Millipore) were visualized with primary antibodies specific for the COOH terminus of KAP1 (15), {gamma}KAP1 (raised to phosphopeptide; Fig. 1A ), tubulin (Calbiochem-EMD Biosciences), and actin (Sigma).


Figure 1
View larger version (33K):
[in this window]
[in a new window]

  		Figure 1. A, a model depicting the domains on KAP1 used for repression and the sequence where KAP1 is phosphorylated following DNA damage. A sequence comparison of the region encompassing the KAP1 phosphorylation site between human and murine KAP1, and KAP1 with its other TIF family members. Analysis of nuclear extracts isolated from U2OS cells at different time points following treatment with 9-Gy ionizing radiation (IR; B) or 100 nmol/L neocarzinostatin (NCS; C) via Western blotting (Wb) with antibodies specific for {gamma}KAP1 (top), KAP1 (middle), and tubulin (B, bottom) or actin (C, bottom).

 
Immunofluorescence. U2OS cells plated on glass coverslips were washed once in PBS and fixed (10 minutes at room temperature) in a 4% paraformaldehyde solution. After two washes in PBS, the fixed cells were permeabilized in 0.2% Triton solution (15 minutes at room temperature). After two washes in PBS, four drops of Signal Enhancer solution (Molecular Probes-Invitrogen) were added to each coverslip (30 minutes at room temperature). After two washes in PBS, primary antibodies specific for KAP1 phosphorylated at Ser824, H2AX phosphorylated at Ser139 (Upstate-Millipore), 53BP1 (gift from T. Halazonetis), TopBP1 (BD Biosciences), and BRCA1 (Ab1; Calbiochem) were added (overnight at 4°C). Coverslips were washed, secondary antibodies (Molecular Probes-Invitrogen) were added (1 hour at 4°C), washed again, and then mounted onto slides. The immunostaining was visualized with scanning laser confocal microscopy (Zeiss LSM-510 with Meta function).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Phosphorylation of KAP1 at Ser824 is an early event in the DNA damage response. Very little is known about how the >500 KRAB-ZFPs are regulated in the cell, especially after genotoxic stress. One major clue arose from the finding that the KRAB-ZFP ZBRK1 mediated the repression of the damage responsive gene growth arrest and DNA damage clone 45 (gadd45) through an association with BRCA1 (17). Moreover, in the course of examining SUMO modification of the plant homeodomain and bromodomain, we found a potential target site for phosphorylation, an SQ motif, at Ser824. These observations led us to consider whether KAP1 could be involved in the DNA damage response. This potential site of phosphorylation was conserved between human and mouse and not found among the other TIF1 family members (Fig. 1A). SQ/TQ sites have been shown to be phosphorylated by members of the PIKK kinase family, including ATM, ATR, and DNA-PK. The fact that many of the proteins phosphorylated at these sites are involved in the DNA damage response (3–6) and that SUMOylation and phosphorylation are often coupled led us to examine whether the SQ motif at Ser824 on KAP1 was targeted in vivo. To this end, we generated antiserum to a phosphopeptide representing the potential PIKK target site (Fig. 1A). The specificity of KAP1 (Ser824) antibody was verified using dot blots, phosphopeptide competition assays, and ionizing radiation and neocarzinostatin treatment of KAP1 knockdown U2OS cells (data not shown). Nuclear extracts prepared from cells irradiated or treated with neocarzinostatin showed rapid phosphorylation of KAP1 (Fig. 1B and C).

ATM, ATR, and DNA-PK phosphorylate KAP1 in response to DNA damage. Because the conserved SQ site on KAP1 could be phosphorylated by any of the PIKK family members, it was important to determine which of these stress kinases mediated this event. We examined the level of phosphorylated KAP1 (or {gamma}KAP1) in ATM–/– (AT5BIVA) and DNA-PK–/– (MO59J) fibroblasts treated with 2- and 9-Gy ionizing radiation at different time points following irradiation. KAP1 was phosphorylated in a time- and dose-dependent manner in both FF2425 and MO59K cells (Fig. 2A and C ) whereas damage-induced KAP1 phosphorylation was not diminished in the ATM null or DNA-PK null fibroblasts (Fig. 2B and D). These data suggest that KAP1 phosphorylation can occur in the absence of ATM or DNA-PK.


Figure 2
View larger version (20K):
[in this window]
[in a new window]

  		Figure 2. Analysis of nuclear extracts isolated from FF2425 (A), AT5BIVA (B), MO59K (C), and MO59J (D) cells 5 minutes, 30 minutes, and 3 hours after treatment with 2- and 9-Gy ionizing radiation via Western blotting with antibodies specific for {gamma}KAP1 (top), KAP1 (middle), and tubulin (bottom). The nontransformed fetal fibroblast cell line FF2425 and the DNA-PK+/+ cell line MO59K were used as positive controls for the ATM and DNA-PK null cell lines.

 
To address whether KAP1 is a specific substrate for ATR or all three PIKK family members, we treated DNA-PK–/– and ATM–/– cells with various kinase inhibitors before irradiation. Wortmannin is a nonselective inhibitor for all PIKK family members (18). Pretreatment of cells with wortmannin inhibited KAP1 phosphorylation in response to ionizing radiation (Fig. 3A, lane 8 , and data not shown). Caffeine selectively targets ATM and ATR whereas the inhibitor NU7036 selectively targets DNA-PK (18, 19). Phosphorylation of KAP1 was not diminished in ATM null cells pretreated with NU7026, suggesting that KAP1 could still be phosphorylated in the absence of both ATM and DNA-PK activity (Fig. 3A, lanes 6 and 7). Furthermore, treatment of ATM null cells with caffeine also had no effect on KAP1 phosphorylation, suggesting that ATR was not the principal KAP1 targeting kinase (Fig. 3A, lanes 9 and 10). Taken together, these data suggest that KAP1 may be redundantly targeted for phosphorylation by all three PIKK family members following ionizing radiation. To verify this result, we treated DNA-PK–/– (MO59J) cells with caffeine. Inhibition of ATM and ATR by caffeine blocked KAP1 phosphorylation in the absence of DNA-PK, further implying that KAP1 is phosphorylated by all three PIKK members (Fig. 3B). The ATM/ATR pathway, however, may be dominant in this paradigm as pretreatment of MO59K and U2OS cells with caffeine was able to substantially block KAP1 phosphorylation (Fig. 3C, and data not shown).


Figure 3
View larger version (20K):
[in this window]
[in a new window]

  		Figure 3. A, analysis of nuclear extracts isolated from AT5BIVA cells pretreated with NU7026, wortmannin, or caffeine 1 hour before exposure to 9-Gy ionizing radiation. The extracts were isolated 30 minutes post-ionizing radiation and analyzed via Western blotting with antibodies specific for {gamma}KAP1 (top), KAP1 (middle), or tubulin (A, bottom). MO59J cells (B) and U2OS cells (C) were pretreated with wortmannin or caffeine 1 hour before exposure to 9-Gy ionizing radiation. The extracts were isolated 30 minutes post-ionizing radiation and analyzed via Western blotting with antibodies specific for {gamma}KAP1 (top), KAP1 (middle), or actin (bottom).

 
{gamma}KAP1 colocalizes with 53BP1, {gamma}H2AX, BRCA1, and TopBP1 at DNA damage foci. Because we were able to confirm that KAP1 was phosphorylated in response to ionizing radiation, at least in part, by ATM, we next sought to delineate whether this modification occurred through the colocalization of {gamma}KAP1 with other damage responsive proteins at DNA lesions. {gamma}H2AX and 53BP1 localize to double-stranded break very early during the DNA damage response (3, 5). Using our {gamma}KAP1 (Ser824) antibody, we detected {gamma}KAP1 at damage foci in U2OS cells at 8 hours after irradiation (Fig. 4D, bottom ). The heaviest nuclear staining of {gamma}KAP1 occurred after 30 minutes (Fig. 4A and B, top). Preincubation of fixed cells with the Ser824 phosphopeptide (Fig. 1A) eliminated any detectable {gamma}KAP1 foci (data not shown). Moreover, knockdown of KAP1 in U2OS cells using stably expressed short hairpin RNA also diminished the quantity of {gamma}KAP1 foci (data not shown). After 3 hours, {gamma}KAP1 only resided in damage foci, colocalizing very strongly with both {gamma}H2AX and 53BP1 (Fig. 4A and B, bottom). TopBP1 and BRCA1 also aggregate at DNA lesions (4, 6). Interestingly, {gamma}KAP1 also colocalizes with TopBP1 at 3 hours post-ionizing radiation (Fig. 4C, top). {gamma}KAP1-TopBP1 colocalization begins to diminish at 6 hours post-ionizing radiation (Fig. 4C, bottom) and is undetectable after 8 hours (data not shown). Surprisingly, it is only at 8 hours after irradiation that we see {gamma}KAP1 colocalizing with BRCA1 (Fig. 4D, bottom). Taken together, these data suggest that, like {gamma}H2AX and 53BP1, {gamma}KAP1 localizes early to sites of DNA damage, whereas {gamma}KAP1 associates with TopBP1 and BRCA1 at later time points.


Figure 4
View larger version (30K):
[in this window]
[in a new window]

  		Figure 4. Immunofluorescence of U2OS cells 30 minutes and 3 hours (A and B), 3 and 6 hours (C), and 6 and 8 hours (D) post 9-Gy ionizing radiation. Fixed and permeabilized cells were analyzed with antibodies specific for 53BP1 and {gamma}KAP1 (A), {gamma}H2AX and {gamma}KAP1 (B), TopBP1 and {gamma}KAP1 (C), and BRCA1 and {gamma}KAP1 (D) by confocal microscopy. The sites where two proteins (represented either in red or green) overlap are shown in yellow (A–D, Merge).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
DNAs packaged in chromatin serve as aggregation points for macromolecular protein complexes that function to both activate and silence gene expression. Damaged DNAs also serve as high-affinity sites for the assembly of large, heterogeneous protein complexes. Currently, it is thought that the large complexes that regulate gene repression and DNA repair share few members. In this study, we present evidence that suggests that the dedicated KRAB-ZFP corepressor KAP1, a key component of a gene silencing complex, is a new substrate for kinases activated by double-stranded breaks. Additionally, we have found that {gamma}KAP1 colocalizes with numerous damage response proteins including {gamma}H2AX, 53BP1, TopBP1, and BRCA1 at DNA lesions with differing kinetics.

Using ATM and DNA-PK null fibroblasts, we found that KAP1 phosphorylation was not dependent on either ATM or DNA-PK alone. Furthermore, KAP1 phosphorylation was abolished using a nonselective inhibitor for PIKK family members (wortmannin) and a selective inhibitor for ATM and ATR (caffeine) in numerous cell lines. However, pretreatment with equivalent doses of caffeine was unable to block KAP1 phosphorylation in ATM null cells. Taken together, these data suggest that KAP1 can be phosphorylated by ATM, DNA-PK, and ATR. Because all of these PIKK family members participate in different modes of repair (homologous recombination, nonhomologous end joining, and ssDNA repair, respectively), these data leave open the possibility that KAP1 may be a general participant in all DNA repair processes. Moreover, the rapid phosphorylation and localization of KAP1 to DNA lesions, which mirror the regulation of H2AX and 53BP1, suggest that KAP1 may be integral for at least the homologous recombination repair pathway. During the course of this work, another group reported that KAP1 was phosphorylated in response to ionizing radiation and neocarzinostatin-mediated DNA damage and that this resulted in a global decondensation of chromatin similar to the decrease in chromatin compaction evident in the absence of KAP1 (20). Together, these data suggest that the phosphorylation of KAP1 may act to inhibit its ability to condense chromatin, which may facilitate DNA repair by increasing access to sites of damage.

Mounting evidence continues to infer that KAP1 may be an important component of the DNA damage response pathway, one which links the gene silencing machinery to the factors that respond to and repair DNA lesions. Indeed, cells that lack KAP1 have been shown to exhibit radiosensitivity (20). Future studies should help illuminate the function of KAP1 in the DNA damage response and clarify what role gene silencing machinery plays within the DNA repair paradigm.


   Acknowledgments
 
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.

Received 11/ 8/06. Accepted 11/ 9/06.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Ziv Y, Bar-Shira A, Pecker I, et al. Recombinant ATM protein complements the cellular A-T phenotype. Oncogene 1997;15:159–67.[CrossRef][Medline]
  2. Morrison C, Sonoda E, Takao N, Shinohara A, Yamamoto K, Takeda S. The controlling role of ATM in homologous recombinational repair of DNA damage. EMBO J 2000;19:463–71.[CrossRef][Medline]
  3. Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ. ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 2001;276:42462–7.[Abstract/Free Full Text]
  4. Yamane K, Wu X, Chen J. A DNA damage-regulated BRCT-containing protein, TopBP1, is required for cell survival. Mol Cell Biol 2002;22:555–66.[Abstract/Free Full Text]
  5. Anderson L, Henderson C, Adachi Y. Phosphorylation and rapid relocalization of 53BP1 to nuclear foci upon DNA damage. Mol Cell Biol 2001;21:1719–29.[Abstract/Free Full Text]
  6. Cortez D, Wang Y, Qin J, Elledge SJ. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 1999;286:1162–6.[Abstract/Free Full Text]
  7. Andegeko Y, Moyal L, Mittelman L, Tsarfaty I, Shiloh Y, Rotman G. Nuclear retention of ATM at sites of DNA double strand breaks. J Biol Chem 2001;276:38224–30.[Abstract/Free Full Text]
  8. Allen C, Halbrook J, Nickoloff JA. Interactive competition between homologous recombination and non-homologous end joining. Mol Cancer Res 2003;1:913–20.[Abstract/Free Full Text]
  9. Jhappan C, Morse HC III, Fleischmann RD, Gottesman MM, Merlino G. DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus. Nat Genet 1997;17:483–6.[CrossRef][Medline]
  10. Ward IM, Minn K, Chen J. UV-induced ataxia-telangiectasia-mutated and Rad3-related (ATR) activation requires replication stress. J Biol Chem 2004;279:9677–80.[Abstract/Free Full Text]
  11. Sripathy SP, Stevens J, Schultz DC. The KAP1 corepressor functions to coordinate the assembly of de novo HP1 demarcated microenvironments of heterochromatin required for KRAB zinc finger protein mediated transcriptional repression. Mol Cell Biol 2006;26:8623–38.[Abstract/Free Full Text]
  12. Peng H, Begg GE, Schultz DC, et al. Reconstitution of the KRAB-KAP-1 repressor complex: a model system for defining the molecular anatomy of RING-B box-coiled-coil domain-mediated protein-protein interactions. J Mol Biol 2000;295:1139–62.[CrossRef][Medline]
  13. Lechner MS, Begg GE, Speicher DW, Rauscher FJ III. Molecular determinants for targeting heterochromatin protein 1-mediated gene silencing: direct chromoshadow domain-KAP-1 corepressor interaction is essential. Mol Cell Biol 2000;20:6449–65.[Abstract/Free Full Text]
  14. Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ III. SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev 2002;16:919–32.[Abstract/Free Full Text]
  15. Schultz DC, Friedman JR, Rauscher FJ III. Targeting histone deacetylase complexes via KRAB-zinc finger proteins: the PHD and bromodomains of KAP-1 form a cooperative unit that recruits a novel isoform of the Mi-2{alpha} subunit of NuRD. Genes Dev 2001;15:428–43.[Abstract/Free Full Text]
  16. Klenova E, Chernukhin I, Inoue T, Shamsuddin S, Norton J. Immunoprecipitation techniques for the analysis of transcription factor complexes. Methods 2002;26:254–9.[CrossRef][Medline]
  17. Zheng L, Pan H, Li S, et al. Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1. Mol Cell 2000;6:757–68.[CrossRef][Medline]
  18. Deriano L, Guipaud O, Merle-Beral H, et al. Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nonhomologous end-joining DNA repair pathway. Blood 2005;105:4776–83.[Abstract/Free Full Text]
  19. Sarkaria JN, Busby EC, Tibbetts RS, et al. Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res 1999;59:4375–82.[Abstract/Free Full Text]
  20. Ziv Y, Bielopolski D, Galanty Y, et al. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM-and KAP-1 dependent pathway. Nat Cell Biol 2006;8:870–6.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Mol. Cell. Biol.Home page
Z. Hou, H. Peng, K. Ayyanathan, K.-P. Yan, E. M. Langer, G. D. Longmore, and F. J. Rauscher III
The LIM Protein AJUBA Recruits Protein Arginine Methyltransferase 5 To Mediate SNAIL-Dependent Transcriptional Repression
Mol. Cell. Biol., May 15, 2008; 28(10): 3198 - 3207.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
X. Li, Y.-K. Lee, J.-C. Jeng, Y. Yen, D. C. Schultz, H.-M. Shih, and D. K. Ann
Role for KAP1 Serine 824 Phosphorylation and Sumoylation/Desumoylation Switch in Regulating KAP1-mediated Transcriptional Repression
J. Biol. Chem., December 14, 2007; 282(50): 36177 - 36189.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
B. Yang, S. M. O'Herrin, J. Wu, S. Reagan-Shaw, Y. Ma, K. M.R. Bhat, C. Gravekamp, V. Setaluri, N. Peters, F. M. Hoffmann, et al.
MAGE-A, mMage-b, and MAGE-C Proteins Form Complexes with KAP1 and Suppress p53-Dependent Apoptosis in MAGE-Positive Cell Lines
Cancer Res., October 15, 2007; 67(20): 9954 - 9962.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Wang, F. J. Rauscher III, W. D. Cress, and J. Chen
Regulation of E2F1 Function by the Nuclear Corepressor KAP1
J. Biol. Chem., October 12, 2007; 282(41): 29902 - 29909.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by White, D. E.
Right arrow Articles by Rauscher, F. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by White, D. E.
Right arrow Articles by Rauscher, F. J., III

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation