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PMID: 19481982 Published · ppublish English Journal Article Review

14-3-3 proteins, FHA domains and BRCT domains in the DNA damage response.

DNA repair ·Vol. 8 ·No. 9 ·2009-09-02 ·Pages 1009-17

Mohammad DH, Yaffe MB

Abstract

The DNA damage response depends on the concerted activity of protein serine/threonine kinases and modular phosphoserine/threonine-binding domains to relay the damage signal and recruit repair proteins. The PIKK family of protein kinases, which includes ATM/ATR/DNA-PK, preferentially phosphorylate Ser-Gln sites, while their basophilic downstream effecter kinases, Chk1/Chk2/MK2 preferentially phosphorylate hydrophobic-X-Arg-X-X-Ser/Thr-hydrophobic sites. A subset of tandem BRCT domains act as phosphopeptide binding modules that bind to ATM/ATR/DNA-PK substrates after DNA damage. Conversely, 14-3-3 proteins interact with substrates of Chk1/Chk2/MK2. FHA domains have been shown to interact with substrates of ATM/ATR/DNA-PK and CK2. In this review we consider how substrate phosphorylation together with BRCT domains, FHA domains and 14-3-3 proteins function to regulate ionizing radiation-induced nuclear foci and help to establish the G(2)/M checkpoint. We discuss the role of MDC1 a molecular scaffold that recruits early proteins to foci, such as NBS1 and RNF8, through distinct phosphodependent interactions. In addition, we consider the role of 14-3-3 proteins and the Chk2 FHA domain in initiating and maintaining cell cycle arrest.

MeSH Terms
14-3-3 Proteins/metabolism Animals Cell Cycle/radiation effects Cell Nucleus/metabolism,radiation effects DNA Damage Humans Protein Structure, Tertiary Radiation, Ionizing
Chemicals
14-3-3 Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Mohammad Duaa H
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Yaffe Michael B
References (99)
99 references, click to expand
  1. 14-3-3 activation of DNA binding of p53 by enhancing its association into tetramers.
    Nucleic Acids Res. 2008 Oct;36(18):5983-91 PMID: 18812399
  2. Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine.
    Cell. 1996 Mar 22;84(6):889-97 PMID: 8601312
  3. Chk2 activation and phosphorylation-dependent oligomerization.
    Mol Cell Biol. 2002 Jun;22(12):4419-32 PMID: 12024051
  4. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.
    Science. 1999 Dec 24;286(5449):2528-31 PMID: 10617473
  5. 14-3-3sigma controls mitotic translation to facilitate cytokinesis.
    Nature. 2007 Mar 15;446(7133):329-32 PMID: 17361185
  6. 14-3-3 proteins act as negative regulators of the mitotic inducer Cdc25 in Xenopus egg extracts.
    Mol Biol Cell. 1998 Feb;9(2):345-54 PMID: 9450960
  7. The BRCT domain is a phospho-protein binding domain.
    Science. 2003 Oct 24;302(5645):639-42 PMID: 14576433
  8. 14-3-3 acts as an intramolecular bridge to regulate cdc25B localization and activity.
    J Biol Chem. 2003 Aug 1;278(31):28580-7 PMID: 12764136
  9. SMG7 is a 14-3-3-like adaptor in the nonsense-mediated mRNA decay pathway.
    Mol Cell. 2005 Feb 18;17(4):537-47 PMID: 15721257
  10. Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2.
    Curr Opin Cell Biol. 2009 Apr;21(2):245-55 PMID: 19230643
  11. DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1.
    Nat Cell Biol. 2002 Dec;4(12):993-7 PMID: 12447390
  12. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response.
    Science. 2007 May 25;316(5828):1194-8 PMID: 17525340
  13. MDC1 is required for the intra-S-phase DNA damage checkpoint.
    Nature. 2003 Feb 27;421(6926):952-6 PMID: 12607003
  14. Association of the cyclin-dependent kinases and 14-3-3 sigma negatively regulates cell cycle progression.
    J Biol Chem. 2000 Jul 28;275(30):23106-12 PMID: 10767298
  15. A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM.
    Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13182-7 PMID: 16141325
  16. Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage.
    Nucleic Acids Res. 2007;35(16):5312-22 PMID: 17690115
  17. Detection of a tandem BRCT in Nbs1 and Xrs2 with functional implications in the DNA damage response.
    Bioinformatics. 2006 Jun 1;22(11):1289-92 PMID: 16522671
  18. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.
    Science. 2007 May 25;316(5828):1160-6 PMID: 17525332
  19. Regulation of the Chk2 protein kinase by oligomerization-mediated cis- and trans-phosphorylation.
    Mol Cancer Res. 2003 Jun;1(8):598-609 PMID: 12805407
  20. The FHA domain is a modular phosphopeptide recognition motif.
    Mol Cell. 1999 Sep;4(3):387-94 PMID: 10518219
  21. ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins.
    Nat Genet. 1998 Jun;19(2):175-8 PMID: 9620776
  22. From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair.
    FEBS Lett. 1997 Jan 2;400(1):25-30 PMID: 9000507
  23. Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage.
    EMBO Rep. 2008 Aug;9(8):795-801 PMID: 18583988
  24. MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage.
    J Biol Chem. 2007 Nov 30;282(48):35416-23 PMID: 17925396
  25. How do 14-3-3 proteins work?-- Gatekeeper phosphorylation and the molecular anvil hypothesis.
    FEBS Lett. 2002 Feb 20;513(1):53-7 PMID: 11911880
  26. 14-3-3 binding regulates catalytic activity of human Wee1 kinase.
    Cell Growth Differ. 2001 Dec;12(12):581-9 PMID: 11751453
  27. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites.
    Science. 2007 May 25;316(5828):1198-202 PMID: 17525341
  28. Distinct BRCT domains in Mcph1/Brit1 mediate ionizing radiation-induced focus formation and centrosomal localization.
    Oncogene. 2008 Jan 3;27(1):139-44 PMID: 17599047
  29. Checkpoint kinase 1-mediated phosphorylation of Cdc25C and bad proteins are involved in antitumor effects of loratadine-induced G2/M phase cell-cycle arrest and apoptosis.
    Mol Carcinog. 2006 Jul;45(7):461-78 PMID: 16649252
  30. MDC1/NFBD1: a key regulator of the DNA damage response in higher eukaryotes.
    DNA Repair (Amst). 2004 Aug-Sep;3(8-9):953-7 PMID: 15279781
  31. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly.
    Cell. 2007 Nov 30;131(5):901-14 PMID: 18001825
  32. Structural determinants of 14-3-3 binding specificities and regulation of subcellular localization of 14-3-3-ligand complexes: a comparison of the X-ray crystal structures of all human 14-3-3 isoforms.
    Semin Cancer Biol. 2006 Jun;16(3):173-82 PMID: 16678437
  33. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.
    Nature. 2003 Jan 30;421(6922):499-506 PMID: 12556884
  34. CCDC98 is a BRCA1-BRCT domain-binding protein involved in the DNA damage response.
    Nat Struct Mol Biol. 2007 Aug;14(8):710-5 PMID: 17643122
  35. C-terminal recognition by 14-3-3 proteins for surface expression of membrane receptors.
    J Biol Chem. 2005 Oct 28;280(43):36263-72 PMID: 16123035
  36. Accumulation of Pax2 transactivation domain interaction protein (PTIP) at sites of DNA breaks via RNF8-dependent pathway is required for cell survival after DNA damage.
    J Biol Chem. 2009 Mar 13;284(11):7284-93 PMID: 19124460
  37. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.
    Cell. 1997 Oct 17;91(2):231-41 PMID: 9346240
  38. MCPH1/BRIT1 cooperates with E2F1 in the activation of checkpoint, DNA repair and apoptosis.
    EMBO Rep. 2008 Sep;9(9):907-15 PMID: 18660752
  39. Localization of human Cdc25C is regulated both by nuclear export and 14-3-3 protein binding.
    Oncogene. 2001 Apr 5;20(15):1839-51 PMID: 11313932
  40. Human PTIP facilitates ATM-mediated activation of p53 and promotes cellular resistance to ionizing radiation.
    J Biol Chem. 2004 Dec 31;279(53):55562-9 PMID: 15456759
  41. MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation.
    Mol Cell. 2005 Jan 7;17(1):37-48 PMID: 15629715
  42. Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2.
    Mol Cell. 2002 May;9(5):1045-54 PMID: 12049740
  43. 14-3-3 proteins in cell cycle regulation.
    Semin Cancer Biol. 2006 Jun;16(3):183-92 PMID: 16697662
  44. Positive regulation of Wee1 by Chk1 and 14-3-3 proteins.
    Mol Biol Cell. 2001 Mar;12(3):551-63 PMID: 11251070
  45. Structure of the FHA1 domain of yeast Rad53 and identification of binding sites for both FHA1 and its target protein Rad9.
    J Mol Biol. 2000 Dec 15;304(5):941-51 PMID: 11124038
  46. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks.
    Cell. 2005 Dec 29;123(7):1213-26 PMID: 16377563
  47. Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization.
    J Biol Chem. 2002 Aug 9;277(32):28706-13 PMID: 12042314
  48. BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly.
    Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15105-9 PMID: 16217032
  49. Phosphorylation of threonine 68 promotes oligomerization and autophosphorylation of the Chk2 protein kinase via the forkhead-associated domain.
    J Biol Chem. 2002 May 31;277(22):19389-95 PMID: 11901158
  50. Subcellular targeting of p33ING1b by phosphorylation-dependent 14-3-3 binding regulates p21WAF1 expression.
    Mol Cell Biol. 2006 Apr;26(8):2947-54 PMID: 16581770
  51. MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways.
    Nature. 2003 Feb 27;421(6926):957-61 PMID: 12607004
  52. Cdc25B activity is regulated by 14-3-3.
    Oncogene. 2001 Jul 19;20(32):4393-401 PMID: 11466620
  53. BRCT domain-containing protein PTIP is essential for progression through mitosis.
    Mol Cell Biol. 2003 Mar;23(5):1666-73 PMID: 12588986
  54. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase.
    Science. 2007 Dec 7;318(5856):1637-40 PMID: 18006705
  55. A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins.
    FASEB J. 1997 Jan;11(1):68-76 PMID: 9034168
  56. MDC1 is a mediator of the mammalian DNA damage checkpoint.
    Nature. 2003 Feb 27;421(6926):961-6 PMID: 12607005
  57. Structure of a second BRCT domain identified in the nijmegen breakage syndrome protein Nbs1 and its function in an MDC1-dependent localization of Nbs1 to DNA damage sites.
    J Mol Biol. 2008 Aug 29;381(2):361-72 PMID: 18582474
  58. Dynamic assembly and sustained retention of 53BP1 at the sites of DNA damage are controlled by Mdc1/NFBD1.
    J Cell Biol. 2005 Jul 18;170(2):201-11 PMID: 16009723
  59. MDC1 regulates intra-S-phase checkpoint by targeting NBS1 to DNA double-strand breaks.
    Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11200-5 PMID: 18678890
  60. Constitutive phosphorylation of MDC1 physically links the MRE11-RAD50-NBS1 complex to damaged chromatin.
    J Cell Biol. 2008 Apr 21;181(2):227-40 PMID: 18411308
  61. 14-3-3 family members act coordinately to regulate mitotic progression.
    Cell Cycle. 2004 May;3(5):672-7 PMID: 15107609
  62. Phosphorylation of SDT repeats in the MDC1 N terminus triggers retention of NBS1 at the DNA damage-modified chromatin.
    J Cell Biol. 2008 Apr 21;181(2):213-26 PMID: 18411307
  63. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins.
    Cell. 2007 Nov 30;131(5):887-900 PMID: 18001824
  64. Binding of 14-3-3 proteins and nuclear export control the intracellular localization of the mitotic inducer Cdc25.
    Genes Dev. 1999 May 1;13(9):1067-72 PMID: 10323858
  65. Structure of the BRCT repeats of BRCA1 bound to a BACH1 phosphopeptide: implications for signaling.
    Mol Cell. 2004 May 7;14(3):405-12 PMID: 15125843
  66. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response.
    Science. 2007 May 25;316(5828):1202-5 PMID: 17525342
  67. The human Myt1 kinase preferentially phosphorylates Cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex.
    Mol Cell Biol. 1997 Feb;17(2):571-83 PMID: 9001210
  68. p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage.
    Cancer Cell. 2007 Feb;11(2):175-89 PMID: 17292828
  69. Specific interaction between 14-3-3 isoforms and the human CDC25B phosphatase.
    Oncogene. 2000 Mar 2;19(10):1257-65 PMID: 10713667
  70. Structure of the BRCT repeat domain of MDC1 and its specificity for the free COOH-terminal end of the gamma-H2AX histone tail.
    J Biol Chem. 2005 Sep 16;280(37):32053-6 PMID: 16049003
  71. Chk1 and Chk2 kinases in checkpoint control and cancer.
    Cancer Cell. 2003 May;3(5):421-9 PMID: 12781359
  72. The G(2) DNA damage checkpoint targets both Wee1 and Cdc25.
    J Cell Sci. 2000 May;113 ( Pt 10):1727-36 PMID: 10769204
  73. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.
    Nat Genet. 1994 Dec;8(4):387-91 PMID: 7894491
  74. Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1.
    J Biol Chem. 2004 Aug 13;279(33):34091-4 PMID: 15220350
  75. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216.
    Science. 1997 Sep 5;277(5331):1501-5 PMID: 9278512
  76. A structural basis for 14-3-3sigma functional specificity.
    J Biol Chem. 2005 May 13;280(19):18891-8 PMID: 15731107
  77. Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage.
    Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20759-63 PMID: 18077395
  78. The FHA domain: a putative nuclear signalling domain found in protein kinases and transcription factors.
    Trends Biochem Sci. 1995 Sep;20(9):347-9 PMID: 7482699
  79. 14-3-3sigma is a p53-regulated inhibitor of G2/M progression.
    Mol Cell. 1997 Dec;1(1):3-11 PMID: 9659898
  80. H2AX: the histone guardian of the genome.
    DNA Repair (Amst). 2004 Aug-Sep;3(8-9):959-67 PMID: 15279782
  81. Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains.
    J Biol Chem. 2003 Dec 26;278(52):52914-8 PMID: 14578343
  82. The structural basis for 14-3-3:phosphopeptide binding specificity.
    Cell. 1997 Dec 26;91(7):961-71 PMID: 9428519
  83. NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain.
    Curr Biol. 2002 Oct 29;12(21):1846-51 PMID: 12419185
  84. Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase.
    Science. 1992 Sep 25;257(5078):1955-7 PMID: 1384126
  85. Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange.
    EMBO J. 2006 Jul 12;25(13):3179-90 PMID: 16794575
  86. BRCT repeats as phosphopeptide-binding modules involved in protein targeting.
    Science. 2003 Oct 24;302(5645):636-9 PMID: 14576432
  87. Cell cycle checkpoint signaling through the ATM and ATR kinases.
    Genes Dev. 2001 Sep 1;15(17):2177-96 PMID: 11544175
  88. 14-3-3 zeta protein binds to the carboxyl half of mouse wee1 kinase.
    Biochem Biophys Res Commun. 1997 Jan 13;230(2):262-5 PMID: 9016762
  89. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer.
    Nat Struct Mol Biol. 2004 Jun;11(6):512-8 PMID: 15133502
  90. Megabase chromatin domains involved in DNA double-strand breaks in vivo.
    J Cell Biol. 1999 Sep 6;146(5):905-16 PMID: 10477747
  91. 14-3-3 suppresses the nuclear localization of threonine 157-phosphorylated p27(Kip1).
    EMBO J. 2004 May 5;23(9):1934-42 PMID: 15057270
  92. ATM phosphorylates histone H2AX in response to DNA double-strand breaks.
    J Biol Chem. 2001 Nov 9;276(45):42462-7 PMID: 11571274
  93. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139.
    J Biol Chem. 1998 Mar 6;273(10):5858-68 PMID: 9488723
  94. Microcephalin/MCPH1 associates with the Condensin II complex to function in homologous recombination repair.
    J Biol Chem. 2008 Oct 24;283(43):29586-92 PMID: 18718915
  95. Chk2 oligomerization studied by phosphopeptide ligation: implications for regulation and phosphodependent interactions.
    J Biol Chem. 2008 Dec 19;283(51):36019-30 PMID: 18948271
  96. PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex.
    J Biol Chem. 2007 Jul 13;282(28):20395-406 PMID: 17500065
  97. NFBD1/MDC1 regulates ionizing radiation-induced focus formation by DNA checkpoint signaling and repair factors.
    FASEB J. 2003 Oct;17(13):1842-8 PMID: 14519663
  98. Checkpoint kinase 2 (Chk2) monomers or dimers phosphorylate Cdc25C after DNA damage regardless of threonine 68 phosphorylation.
    J Biol Chem. 2002 Dec 13;277(50):48418-26 PMID: 12386164
  99. DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity.
    Mol Cell Biol. 2007 Dec;27(24):8502-9 PMID: 17923702
Article Info
Journal
DNA repair
Abbr.
DNA Repair (Amst)
ISSN
1568-7856
DOI
10.1016/j.dnarep.2009.04.004
Published
2009-09-02
Epub
2009-00-29
Pages
1009-17
Language
English
Region
Netherlands
NLM ID
101139138
PMCID
PMC3263375
Subset
IM
Grants
NCI NIH HHS · U54 CA112967-07 · United States
NIEHS NIH HHS · R01 ES015339 · United States
NIGMS NIH HHS · R01 GM060594 · United States
NCI NIH HHS · U54 CA112967 · United States
NIGMS NIH HHS · R01 GM060594-09 · United States
NIEHS NIH HHS · R01 ES015339-05 · United States
External Links
PubMed source DOI: 10.1016/j.dnarep.2009.04.004 PMC Full Text View journal details
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