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Cited by 49

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Dissecting the role of p53 phosphorylation in homologous recombination provides new clues for gain-of-function mutants

Restle, Anja, Färber, Martin, Baumann, Cindy, Böhringer, Michael, Scheidtmann, Karl Heinz, Müller-Tidow, Carsten, Wiesmüller, Lisa·2008·Nucleic Acids Research
DOI 10.1093/nar/gkn503
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Abstract

Regulation of homologous recombination (HR) represents the best-characterized DNA repair function of p53. The role of p53 phosphorylation in DNA repair is largely unknown. Here, we show that wild-type p53 repressed repair of DNA double-strand breaks (DSBs) by HR in a manner partially requiring the ATM/ATR phosphorylation site, serine 15. Cdk-mediated phosphorylation of serine 315 was dispensable for this anti-recombinogenic effect. However, without targeted cleavage of the HR substrate, serine 315 phosphorylation was necessary for the activation of topoisomerase I-dependent HR by p53. Moreover, overexpression of cyclin A1, which mimics the situation in tumors, inappropriately stimulated DSB-induced HR in the presence of oncogenic p53 mutants (not Wtp53). This effect required cyclin A1/cdk-mediated phosphorylation for stable complex formation with topoisomerase I. We conclude that p53 mutants have lost the balance between activation and repression of HR, which results in a net increase of potentially mutagenic DNA rearrangements. Our data provide new insight into the mechanism underlying gain-of-function of mutant p53 in genomic instability.

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Research works printed but not linked: 59

  1. Vogelstein, 2000, Surfing the p53 network, Nature, 408, 307, 10.1038/35042675 · DOI · Paper page
  2. Saito, 2003, Phosphorylation site interdependence of human p53 post-translational modifications in response to stress, J. Biol. Chem., 278, 37536, 10.1074/jbc.M305135200 · DOI · Paper page
  3. Fuchs, 1995, p53 phosphorylation mutants retain transcription activity, Oncogene, 10, 789
  4. Thompson, 2004, Phosphorylation of p53 on key serines is dispensable for transcriptional activation and apoptosis, J. Biol. Chem., 279, 53015, 10.1074/jbc.M410233200 · DOI · Paper page
  5. Jackson, 2004, Limited role of N-terminal residues in the activation of transcription by p53, Oncogene, 23, 4477, 10.1038/sj.onc.1207575 · DOI
  6. Sengupta, 2003, BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination, EMBO J., 22, 1210, 10.1093/emboj/cdg114 · DOI · Paper page
  7. Restle, 2005, Differences in the association of p53 phosphorylated on serine 15 and key enzymes of homologous recombination, Oncogene, 24, 4380, 10.1038/sj.onc.1208639 · DOI
  8. Linke, 2003, p53 interacts with hRAD51 and hRAD54, and directly modulates homologous recombination, Cancer Res., 63, 2596
  9. Bertrand, 2004, P53's double life: transactivation-independent repression of homologous recombination, Trends Genet., 20, 235, 10.1016/j.tig.2004.04.003 · DOI
  10. Arias-Lopez, 2006, p53 modulates homologous recombination by transcriptional regulation of the RAD51 gene, EMBO Rep., 7, 219, 10.1038/sj.embor.7400587 · DOI · Paper page
  11. Boehden, 2005, Wild-type p53 stimulates homologous recombination upon sequence-specific binding to the ribosomal gene cluster repeat, Oncogene, 24, 4183, 10.1038/sj.onc.1208592 · DOI
  12. Boehden, 2004, Recombination at chromosomal sequences involved in leukaemogenic rearrangements is differentially regulated by p53, Carcinogenesis, 25, 1305, 10.1093/carcin/bgh092 · DOI
  13. Baumann, 2006, Poly(ADP-RIBOSE) polymerase-1 (Parp-1) antagonizes topoisomerase I-dependent recombination stimulation by p53, Nucleic Acids Res., 34, 1036, 10.1093/nar/gkj509 · DOI
  14. Subramanian, 2005, Modulation of p53 binding to Holliday junctions and 3-cytosine bulges by phosphorylation events, Biochemistry, 44, 2536, 10.1021/bi048700u · DOI
  15. Akyüz, 2002, DNA substrate dependence of the p53-mediated regulation of double-strand break repair, Mol. Cell Biol., 22, 6306, 10.1128/MCB.22.17.6306-6317.2002 · DOI · Paper page
  16. Brummelkamp, 2002, A system for stable expression of short interfering RNAs in mammalian cells, Science, 296, 550, 10.1126/science.1068999 · DOI · Paper page
  17. Müller-Tidow, 2004, The cyclin A1-CDK2 complex regulates DNA double-strand break repair, Mol. Cell Biol., 24, 8917, 10.1128/MCB.24.20.8917-8928.2004 · DOI
  18. Lambert, 2000, Characterization of mammalian RAD51 double strand break repair using non-lethal dominant-negative forms, EMBO J., 19, 3090, 10.1093/emboj/19.12.3090 · DOI
  19. Grandori, 2003, Werner syndrome protein limits MYC-induced cellular senescence, Genes Dev., 17, 1569, 10.1101/gad.1100303 · DOI · Paper page
  20. Zink, 2002, Association of p53 and MSH2 with recombinative repair complexes during S-phase, Oncogene, 21, 4788, 10.1038/sj.onc.1205614 · DOI
  21. Sarkaria, 1999, Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine, Cancer Res., 59, 4375
  22. Mahdi, 1998, Rescue of K562 cells from MDM2-modulated p53-dependent apoptosis by growth factor-induced differentiation, Biol. Chem., 90, 15
  23. Saintigny, 1999, Mutant p53 proteins stimulate spontaneous and radiation-induced intrachromosomal homologous recombination independently of the alteration of the transactivation activity and of the G1 checkpoint, Oncogene, 18, 3553, 10.1038/sj.onc.1202941 · DOI
  24. Won, 2006, Small molecule-based reversible reprogramming of cellular lifespan, Nat. Chem. Biol., 2, 369, 10.1038/nchembio800 · DOI
  25. Gobert, 1999, The interaction between p53 and DNA topoisomerase I is regulated differently in cells with wild-type and mutant p53, Proc. Natl Acad. Sci. USA, 96, 10355, 10.1073/pnas.96.18.10355 · DOI
  26. Boehden, 2003, p53 mutated in the transactivation domain retains regulatory functions in homology-directed double-strand break repair, Oncogene, 22, 4111, 10.1038/sj.onc.1206632 · DOI
  27. Wesierska-Gadek, 2004, Cell cycle arrest induced in human breast cabcer celly by cyclin-dependent kinase inhibitors: a comparison of the effects exerted by roscovitine and olomoucine, Pol. J. Pharmacol., 56, 635
  28. Rothkamm, 2003, Pathways of DNA double-strand break repair during the mammalian cell cycle, Mol. Cell Biol., 23, 5706, 10.1128/MCB.23.16.5706-5715.2003 · DOI · Paper page
  29. Fogal, 2005, Cell cycle-dependent nuclear retention of p53 by E2F1 requires phosphorylation of p53 at Ser315, EMBO J., 24, 2768, 10.1038/sj.emboj.7600735 · DOI
  30. Yang, 1999, Functions of cyclin A1 in the cell cycle and its interactions with transcription factor E2F-1 and the Rb family of proteins, Mol. Cell Biol., 19, 2400, 10.1128/MCB.19.3.2400 · DOI
  31. Blander, 1999, Physical and functional interaction between p53 and the Werner's syndrome protein, J. Biol. Chem., 274, 29463, 10.1074/jbc.274.41.29463 · DOI · Paper page
  32. Lebel, 1999, The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I, J. Biol. Chem., 274, 37795, 10.1074/jbc.274.53.37795 · DOI
  33. Laine, 2003, Werner protein stimulates topoisomerase I DNA relaxation activity, Cancer Res., 63, 7136
  34. Song, 2007, p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM, Nat. Cell Biol., 9, 573, 10.1038/ncb1571 · DOI · Paper page
  35. El-Hizawi, 2002, Induction of gene amplification as a gain-of-function phenotype of mutant p53 proteins, Cancer Res., 62, 3264
  36. Perkins, 2002, Sensing of intermediates in V(D)J recombination by ATM, Genes Dev., 16, 159, 10.1101/gad.956902 · DOI
  37. Romanova, 2004, The interaction of p53 with replication protein A mediates suppression of homologous recombination, Oncogene, 23, 9025, 10.1038/sj.onc.1207982 · DOI · Paper page
  38. Sengupta, 2004, Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest, J. Cell Biol., 166, 801, 10.1083/jcb.200405128 · DOI
  39. Wang, 1995, Increased and altered DNA binding of human p53 by S and G2/M but not G1 cyclin-dependent kinases, Nature, 376, 88, 10.1038/376088a0 · DOI · Paper page
  40. Luciani, 2000, The C-terminal regulatory domain of p53 contains a functional docking site for cyclin A, J. Mol. Biol., 300, 503, 10.1006/jmbi.2000.3830 · DOI
  41. Larsen, 1999, DNA topoisomerase I in oncology: Dr Jekyll or Mr Hyde ?, Pathol. Oncol. Res., 5, 171, 10.1053/paor.1999.0209 · DOI
  42. Champoux, 1977, Strand breakage by the DNA untwisting enzyme results in covalent attachment of the enzyme to DNA, Proc. Natl Acad. Sci. USA, 74, 3800, 10.1073/pnas.74.9.3800 · doi:10.1073/pnas.74.9.3800
  43. Sekiguchi, 1996, Resolution of Holliday junctions by eukaryotic DNA topoisomerase I, Proc. Natl Acad. Sci. USA, 93, 785, 10.1073/pnas.93.2.785 · DOI
  44. Liao, 2004, Resolution of undistorted symmetric immobile DNA junctions by vaccinia topoisomerase I, Biochemistry, 43, 1520, 10.1021/bi0358061 · doi:10.1021/bi0358061
  45. Gobert, 1996, Modulation of DNA topoisomerase I activity by p53, Biochemistry, 35, 5778, 10.1021/bi952327w · DOI
  46. Albor, 1998, Wildtype and mutant forms of p53 activate human topoisomerase I: a possible mechanism for gain of function in mutants, Cancer Res., 5, 2091
  47. Stephan, 2002, Human topoisomerase I cleavage complexes are repaired by a p53-stimulated recombination-like reaction in vitro, Nucleic Acids Res., 30, 5087, 10.1093/nar/gkf659 · doi:10.1093/nar/gkf659
  48. Roemer, 1999, Mutant p53: gain-of-function oncoproteins and wild-type p53 inactivators, Biol. Chem., 380, 879, 10.1515/BC.1999.108 · DOI
  49. Liu, 1996, Analysis of genomic instability in Li-Fraumeni fibroblasts with germline p53 mutations, Oncogene, 12, 2267
  50. Murphy, 2000, Mutant p53 and genomic instability in a transgenic mouse model of breast cancer, Oncogene, 19, 1045, 10.1038/sj.onc.1203274 · DOI
  51. Müller, 1999, c-myb transactivates the human cyclin A1 promoter and induces cyclin A1 gene expression, Blood, 94, 4255, 10.1182/blood.V94.12.4255 · DOI
  52. Müller, 2000, The aberrant fusion proteins PML-RAR alpha and PLZF-RAR alpha contribute to the overexpression of cyclin A1 in acute promyelocytic leukemia, Blood, 96, 3894, 10.1182/blood.V96.12.3894 · DOI
  53. Coletta, 2004, The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1, Proc. Natl Acad. Sci. USA, 101, 6478, 10.1073/pnas.0401139101 · DOI · Paper page
  54. Müller-Tidow, 2003, Cyclin A1 is highly expressed in aggressive testicular germ cell tumors, Cancer Lett., 190, 89, 10.1016/S0304-3835(02)00582-7 · doi:10.1016/s0304-3835(02)00582-7
  55. Yang, 1999, Cyclin A1 expression in leukemia and normal hematopoietic cells, Blood, 93, 2067
  56. Liao, 2001, Altered myelopoiesis and the development of acute myeloid leukemia in transgenic mice overexpressing cyclin A1, Proc. Natl Acad. Sci. USA, 98, 6853, 10.1073/pnas.121540098 · DOI
  57. Tokumaru, 2004, Inverse correlation between cyclin A1 hyper-methylation and p53 mutation in head and neck cancer identified by reversal of epigenetic silencing, Cancer Res., 64, 5982, 10.1158/0008-5472.CAN-04-0993 · DOI
  58. Bartkova, 2005, DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis, Nature, 434, 864, 10.1038/nature03482 · DOI · Paper page
  59. Armata, 2007, The ataxia telangiectasia-mutated target site ser18 is required for p53-mediated tumor suppression, Cancer Res., 67, 11696, 10.1158/0008-5472.CAN-07-1610 · DOI

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Metadata

Authors
Restle, A., Färber, M., Baumann, C., Böhringer, M., Scheidtmann, K. H., Müller-Tidow, C., & Wiesmüller, L.
Affiliations
  • Department of Obstetrics and Gynecology, University of Ulm, 89075 Ulm,
  • Institute for Genetics, University of Bonn, 53113 Bonn
  • Department of Medicine, Hematology/Oncology, University of Münster, 48129 Münster, Germany
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2008-08-12
Volume
36
Issue
16
Pages
5362-5375
ISSN
  • 1362-4962
  • 0305-1048
DOI
10.1093/nar/gkn503
Cited by
49
References
9
Language
en
Licence
creativecommons.org/licenses/by-nc/2.0/uk/ (vor, 4738 d)
Funders
  • Deutsche Forschungsgemeinschaft (Wi 1376/3-2, Wi 3099/7-1)
  • Landesstiftung Baden-Württemberg (10-1907-Wi 2)
  • Dr Mildred Scheel Stiftung für Krebsforschung (107744)
  • University of Ulm, Germany

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CoChat. (2026). Citation check: Dissecting the role of p53 phosphorylation in homologous recombination provides new clues for gain-of-function mutants. https://app.cochat.ai/papers/10.1093/nar/gkn503
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Restle, A., Färber, M., Baumann, C., Böhringer, M., Scheidtmann, K. H., Müller-Tidow, C., & Wiesmüller, L. (2008). Dissecting the role of p53 phosphorylation in homologous recombination provides new clues for gain-of-function mutants. Nucleic Acids Research. https://doi.org/10.1093/nar/gkn503

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