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PMID: 22531782 Published · ppublish English Journal Article

A new non-catalytic role for ubiquitin ligase RNF8 in unfolding higher-order chromatin structure.

The EMBO journal ·Vol. 31 ·No. 11 ·2012-05-30 ·Pages 2511-27

Luijsterburg MS, Acs K, Ackermann L, Wiegant WW, Bekker-Jensen S, Larsen DH, Khanna KK, van Attikum H, Mailand N, Dantuma NP

Abstract

The ubiquitin ligases RNF8 and RNF168 orchestrate DNA damage signalling through the ubiquitylation of histone H2A and the recruitment of downstream repair factors. Here, we demonstrate that RNF8, but not RNF168 or the canonical H2A ubiquitin ligase RNF2, mediates extensive chromatin decondensation. Our data show that CHD4, the catalytic subunit of the NuRD complex, interacts with RNF8 and is essential for RNF8-mediated chromatin unfolding. The chromatin remodelling activity of CHD4 promotes efficient ubiquitin conjugation and assembly of RNF168 and BRCA1 at DNA double-strand breaks. Interestingly, RNF8-mediated recruitment of CHD4 and subsequent chromatin remodelling were independent of the ubiquitin-ligase activity of RNF8, but involved a non-canonical interaction with the forkhead-associated (FHA) domain. Our study reveals a new mechanism of chromatin remodelling-assisted ubiquitylation, which involves the cooperation between CHD4 and RNF8 to create a local chromatin environment that is permissive to the assembly of checkpoint and repair machineries at DNA lesions.

MeSH Terms
Animals Autoantigens/metabolism BRCA1 Protein/metabolism Cell Line, Tumor Chromatin/metabolism Chromatin Assembly and Disassembly Cricetinae DNA Breaks, Double-Stranded DNA Helicases/metabolism DNA-Binding Proteins/genetics,metabolism Humans Mi-2 Nucleosome Remodeling and Deacetylase Complex/metabolism Mice Ubiquitin/metabolism Ubiquitin-Protein Ligases/genetics,metabolism Ubiquitination
Chemicals
Autoantigens BRCA1 Protein CHD4 protein, human Chromatin DNA-Binding Proteins RNF8 protein, human Ubiquitin RNF168 protein, human Rnf8 protein, mouse Ubiquitin-Protein Ligases Mi-2 Nucleosome Remodeling and Deacetylase Complex Mi-2beta protein, mouse DNA Helicases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Luijsterburg Martijn S
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Acs Klara
Ackermann Leena
Wiegant Wouter W
Bekker-Jensen Simon
Larsen Dorthe H
Khanna Kum Kum
van Attikum Haico
Mailand Niels
Dantuma Nico P
References (57)
57 references, click to expand
  1. ATP-dependent chromatin remodeling facilitates nucleotide excision repair of UV-induced DNA lesions in synthetic dinucleosomes.
    EMBO J. 2001 Apr 17;20(8):2004-14 PMID: 11296233
  2. The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks.
    Nat Struct Mol Biol. 2011 Nov 27;18(12):1345-50 PMID: 22120668
  3. Nucleotide excision repair-induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response.
    J Cell Biol. 2009 Sep 21;186(6):835-47 PMID: 19797077
  4. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1.
    Science. 2009 Sep 4;325(5945):1240-3 PMID: 19661379
  5. BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations.
    J Cell Biol. 2001 Dec 10;155(6):911-21 PMID: 11739404
  6. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins.
    Cell. 2007 Nov 30;131(5):887-900 PMID: 18001824
  7. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins.
    Cell. 2009 Feb 6;136(3):435-46 PMID: 19203579
  8. KAP-1 phosphorylation regulates CHD3 nucleosome remodeling during the DNA double-strand break response.
    Nat Struct Mol Biol. 2011 Jun 05;18(7):831-9 PMID: 21642969
  9. Activation of the cellular DNA damage response in the absence of DNA lesions.
    Science. 2008 Jun 13;320(5882):1507-10 PMID: 18483401
  10. Modifying chromatin architecture during the response to DNA breakage.
    Crit Rev Biochem Mol Biol. 2010 Feb;45(1):2-13 PMID: 19874211
  11. The human Mi-2/NuRD complex and gene regulation.
    Oncogene. 2007 Aug 13;26(37):5433-8 PMID: 17694084
  12. ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks.
    Cell. 2010 Jun 11;141(6):970-81 PMID: 20550933
  13. Assembly of multiprotein complexes that control genome function.
    J Cell Biol. 2009 Apr 6;185(1):21-6 PMID: 19332890
  14. UMI, a novel RNF168 ubiquitin binding domain involved in the DNA damage signaling pathway.
    Mol Cell Biol. 2011 Jan;31(1):118-26 PMID: 21041483
  15. Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining.
    Nat Struct Mol Biol. 2010 Sep;17(9):1144-51 PMID: 20802485
  16. DNA damage triggers nucleotide excision repair-dependent monoubiquitylation of histone H2A.
    Genes Dev. 2006 May 15;20(10):1343-52 PMID: 16702407
  17. The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks.
    Nat Cell Biol. 2011 Oct 23;13(11):1376-82 PMID: 22020440
  18. Role of histone H2A ubiquitination in Polycomb silencing.
    Nature. 2004 Oct 14;431(7010):873-8 PMID: 15386022
  19. HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes.
    Nat Cell Biol. 2010 Jan;12(1):80-6; sup pp 1-12 PMID: 20023648
  20. Mechanisms of polycomb gene silencing: knowns and unknowns.
    Nat Rev Mol Cell Biol. 2009 Oct;10(10):697-708 PMID: 19738629
  21. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly.
    Cell. 2007 Nov 30;131(5):901-14 PMID: 18001825
  22. Heterochromatin protein 1 is recruited to various types of DNA damage.
    J Cell Biol. 2009 May 18;185(4):577-86 PMID: 19451271
  23. A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage.
    Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18475-80 PMID: 20937877
  24. Crosstalk between histone modifications during the DNA damage response.
    Trends Cell Biol. 2009 May;19(5):207-17 PMID: 19342239
  25. From silencing to gene expression: real-time analysis in single cells.
    Cell. 2004 Mar 5;116(5):683-98 PMID: 15006351
  26. RAD18 transmits DNA damage signalling to elicit homologous recombination repair.
    Nat Cell Biol. 2009 May;11(5):592-603 PMID: 19396164
  27. Positional stability of single double-strand breaks in mammalian cells.
    Nat Cell Biol. 2007 Jun;9(6):675-82 PMID: 17486118
  28. Ring1B compacts chromatin structure and represses gene expression independent of histone ubiquitination.
    Mol Cell. 2010 May 14;38(3):452-64 PMID: 20471950
  29. 53BP1-dependent robust localized KAP-1 phosphorylation is essential for heterochromatic DNA double-strand break repair.
    Nat Cell Biol. 2010 Feb;12(2):177-84 PMID: 20081839
  30. In vivo localization of DNA sequences and visualization of large-scale chromatin organization using lac operator/repressor recognition.
    J Cell Biol. 1996 Dec;135(6 Pt 2):1685-700 PMID: 8991083
  31. CHD proteins: a diverse family with strong ties.
    Biochem Cell Biol. 2007 Aug;85(4):463-76 PMID: 17713581
  32. Structure of a BRCA1-BARD1 heterodimeric RING-RING complex.
    Nat Struct Biol. 2001 Oct;8(10):833-7 PMID: 11573085
  33. Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler.
    Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13770-4 PMID: 19666485
  34. Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting gamma-H2AX induction.
    EMBO J. 2006 Sep 6;25(17):3986-97 PMID: 16932743
  35. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase.
    Science. 2007 Dec 7;318(5856):1637-40 PMID: 18006705
  36. Chromatin compaction by a polycomb group protein complex.
    Science. 2004 Nov 26;306(5701):1574-7 PMID: 15567868
  37. A cooperative activation loop among SWI/SNF, gamma-H2AX and H3 acetylation for DNA double-strand break repair.
    EMBO J. 2010 Apr 21;29(8):1434-45 PMID: 20224553
  38. The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks.
    Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3166-71 PMID: 19202061
  39. Ageing-related chromatin defects through loss of the NURD complex.
    Nat Cell Biol. 2009 Oct;11(10):1261-7 PMID: 19734887
  40. Chromatin and the DNA damage response: the cancer connection.
    Mol Oncol. 2011 Aug;5(4):349-67 PMID: 21782533
  41. Large-scale chromatin unfolding and remodeling induced by VP16 acidic activation domain.
    J Cell Biol. 1999 Jun 28;145(7):1341-54 PMID: 10385516
  42. Transcriptional activation by tetracyclines in mammalian cells.
    Science. 1995 Jun 23;268(5218):1766-9 PMID: 7792603
  43. ATM mediated phosphorylation of CHD4 contributes to genome maintenance.
    Genome Integr. 2011 Jan 10;2(1):1 PMID: 21219611
  44. Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage.
    Nat Cell Biol. 2003 Mar;5(3):255-60 PMID: 12598907
  45. Symmetry and asymmetry of the RING-RING dimer of Rad18.
    J Mol Biol. 2011 Jul 15;410(3):424-35 PMID: 21549715
  46. Assembly of checkpoint and repair machineries at DNA damage sites.
    Trends Biochem Sci. 2010 Feb;35(2):101-8 PMID: 19875294
  47. 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
  48. The NuRD chromatin-remodeling complex regulates signaling and repair of DNA damage.
    J Cell Biol. 2010 Sep 6;190(5):741-9 PMID: 20805320
  49. Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4.
    EMBO J. 2010 Sep 15;29(18):3130-9 PMID: 20693977
  50. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities.
    Mol Cell. 1998 Dec;2(6):851-61 PMID: 9885572
  51. The chromatin-remodeling factor CHD4 coordinates signaling and repair after DNA damage.
    J Cell Biol. 2010 Sep 6;190(5):731-40 PMID: 20805324
  52. Characterization of the CHD family of proteins.
    Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11472-7 PMID: 9326634
  53. Stochastic and reversible assembly of a multiprotein DNA repair complex ensures accurate target site recognition and efficient repair.
    J Cell Biol. 2010 May 3;189(3):445-63 PMID: 20439997
  54. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage.
    Cell. 2009 Feb 6;136(3):420-34 PMID: 19203578
  55. In vivo HP1 targeting causes large-scale chromatin condensation and enhanced histone lysine methylation.
    Mol Cell Biol. 2005 Jun;25(11):4552-64 PMID: 15899859
  56. Chromatin structure and DNA damage repair.
    Epigenetics Chromatin. 2008 Nov 12;1(1):9 PMID: 19014481
  57. The ACF1 complex is required for DNA double-strand break repair in human cells.
    Mol Cell. 2010 Dec 22;40(6):976-87 PMID: 21172662
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2012.104
Published
2012-05-30
Epub
2012-00-24
Pages
2511-27
Language
English
Region
England
NLM ID
8208664
PMCID
PMC3365417
Subset
IM
External Links
PubMed source DOI: 10.1038/emboj.2012.104 PMC Full Text View journal details
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