| Structural highlights
Function
RNF8_HUMAN E3 ubiquitin-protein ligase that plays a key role in DNA damage signaling via 2 distinct roles: by mediating the 'Lys-63'-linked ubiquitination of histones H2A and H2AX and promoting the recruitment of DNA repair proteins at double-strand breaks (DSBs) sites, and by catalyzing 'Lys-48'-linked ubiquitination to remove target proteins from DNA damage sites. Following DNA DSBs, it is recruited to the sites of damage by ATM-phosphorylated MDC1 and catalyzes the 'Lys-63'-linked ubiquitination of histones H2A and H2AX, thereby promoting the formation of TP53BP1 and BRCA1 ionizing radiation-induced foci (IRIF). Also controls the recruitment of UIMC1-BRCC3 (RAP80-BRCC36) and PAXIP1/PTIP to DNA damage sites. Also recruited at DNA interstrand cross-links (ICLs) sites and catalyzes 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Promotes the formation of 'Lys-63'-linked polyubiquitin chains via interactions with the specific ubiquitin-conjugating UBE2N/UBC13 and ubiquitinates non-histone substrates such as PCNA. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation. Also catalyzes the formation of 'Lys-48'-linked polyubiquitin chains via interaction with the ubiquitin-conjugating UBE2L6/UBCH8, leading to degradation of substrate proteins such as CHEK2, JMJD2A/KDM4A and KU80/XRCC5: it is still unclear how the preference toward 'Lys-48'- versus 'Lys-63'-linked ubiquitination is regulated but it could be due to RNF8 ability to interact with specific E2 specific ligases. For instance, interaction with phosphorylated HERC2 promotes the association between RNF8 and UBE2N/UBC13 and favors the specific formation of 'Lys-63'-linked ubiquitin chains. Promotes non-homologous end joining (NHEJ) by promoting the 'Lys-48'-linked ubiquitination and degradation the of KU80/XRCC5. Following DNA damage, mediates the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF168, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. In addition to its function in damage signaling, also plays a role in higher-order chromatin structure by mediating extensive chromatin decondensation. Involved in the activation of ATM by promoting histone H2B ubiquitination, which indirectly triggers histone H4 'Lys-16' acetylation (H4K16ac), establishing a chromatin environment that promotes efficient activation of ATM kinase. Required in the testis, where it plays a role in the replacement of histones during spermatogenesis. At uncapped telomeres, promotes the joining of deprotected chromosome ends by inducing H2A ubiquitination and TP53BP1 recruitment, suggesting that it may enhance cancer development by aggraving telomere-induced genome instability in case of telomeric crisis. Promotes the assembly of RAD51 at DNA DSBs in the absence of BRCA1 and TP53BP1 Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. May be required for proper exit from mitosis after spindle checkpoint activation and may regulate cytokinesis. May play a role in the regulation of RXRA-mediated transcriptional activity. Not involved in RXRA ubiquitination by UBE2E2.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
DNA-damage signaling utilizes a multitude of posttranslational modifiers as molecular switches to regulate cell-cycle checkpoints, DNA repair, cellular senescence, and apoptosis. Here we show that RNF8, a FHA/RING domain-containing protein, plays a critical role in the early DNA-damage response. We have solved the X-ray crystal structure of the FHA domain structure at 1.35 A. We have shown that RNF8 facilitates the accumulation of checkpoint mediator proteins BRCA1 and 53BP1 to the damaged chromatin, on one hand through the phospho-dependent FHA domain-mediated binding of RNF8 to MDC1, on the other hand via its role in ubiquitylating H2AX and possibly other substrates at damage sites. Moreover, RNF8-depleted cells displayed a defective G2/M checkpoint and increased IR sensitivity. Together, our study implicates RNF8 as a novel DNA-damage-responsive protein that integrates protein phosphorylation and ubiquitylation signaling and plays a critical role in the cellular response to genotoxic stress.
RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly.,Huen MS, Grant R, Manke I, Minn K, Yu X, Yaffe MB, Chen J Cell. 2007 Nov 30;131(5):901-14. Epub 2007 Nov 20. PMID:18001825[25]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ito K, Adachi S, Iwakami R, Yasuda H, Muto Y, Seki N, Okano Y. N-Terminally extended human ubiquitin-conjugating enzymes (E2s) mediate the ubiquitination of RING-finger proteins, ARA54 and RNF8. Eur J Biochem. 2001 May;268(9):2725-32. PMID:11322894
- ↑ Takano Y, Adachi S, Okuno M, Muto Y, Yoshioka T, Matsushima-Nishiwaki R, Tsurumi H, Ito K, Friedman SL, Moriwaki H, Kojima S, Okano Y. The RING finger protein, RNF8, interacts with retinoid X receptor alpha and enhances its transcription-stimulating activity. J Biol Chem. 2004 Apr 30;279(18):18926-34. Epub 2004 Feb 23. PMID:14981089 doi:http://dx.doi.org/10.1074/jbc.M309148200
- ↑ Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C, Lukas J. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell. 2007 Nov 30;131(5):887-900. Epub 2007 Nov 20. PMID:18001824 doi:http://dx.doi.org/10.1016/j.cell.2007.09.040
- ↑ Wang B, Elledge SJ. 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. Epub 2007 Dec 5. PMID:18077395 doi:http://dx.doi.org/0710061104
- ↑ Kolas NK, Chapman JR, Nakada S, Ylanko J, Chahwan R, Sweeney FD, Panier S, Mendez M, Wildenhain J, Thomson TM, Pelletier L, Jackson SP, Durocher D. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science. 2007 Dec 7;318(5856):1637-40. Epub 2007 Nov 15. PMID:18006705 doi:http://dx.doi.org/10.1126/science.1150034
- ↑ Plans V, Guerra-Rebollo M, Thomson TM. Regulation of mitotic exit by the RNF8 ubiquitin ligase. Oncogene. 2008 Feb 28;27(10):1355-65. Epub 2007 Sep 3. PMID:17724460 doi:http://dx.doi.org/1210782
- ↑ Zhang S, Chea J, Meng X, Zhou Y, Lee EY, Lee MY. PCNA is ubiquitinated by RNF8. Cell Cycle. 2008 Nov 1;7(21):3399-404. PMID:18948756
- ↑ Sakasai R, Tibbetts R. RNF8-dependent and RNF8-independent regulation of 53BP1 in response to DNA damage. J Biol Chem. 2008 May 16;283(20):13549-55. Epub 2008 Mar 12. PMID:18337245 doi:http://dx.doi.org/M710197200
- ↑ Stewart GS, Panier S, Townsend K, Al-Hakim AK, Kolas NK, Miller ES, Nakada S, Ylanko J, Olivarius S, Mendez M, Oldreive C, Wildenhain J, Tagliaferro A, Pelletier L, Taubenheim N, Durandy A, Byrd PJ, Stankovic T, Taylor AM, Durocher D. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell. 2009 Feb 6;136(3):420-34. doi: 10.1016/j.cell.2008.12.042. PMID:19203578 doi:10.1016/j.cell.2008.12.042
- ↑ Doil C, Mailand N, Bekker-Jensen S, Menard P, Larsen DH, Pepperkok R, Ellenberg J, Panier S, Durocher D, Bartek J, Lukas J, Lukas C. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell. 2009 Feb 6;136(3):435-46. doi: 10.1016/j.cell.2008.12.041. PMID:19203579 doi:10.1016/j.cell.2008.12.041
- ↑ Gong Z, Cho YW, Kim JE, Ge K, Chen J. 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. Epub 2009 Jan 5. PMID:19124460 doi:http://dx.doi.org/M809158200
- ↑ Wu J, Huen MS, Lu LY, Ye L, Dou Y, Ljungman M, Chen J, Yu X. Histone ubiquitination associates with BRCA1-dependent DNA damage response. Mol Cell Biol. 2009 Feb;29(3):849-60. doi: 10.1128/MCB.01302-08. Epub 2008 Nov, 17. PMID:19015238 doi:http://dx.doi.org/10.1128/MCB.01302-08
- ↑ Shao G, Lilli DR, Patterson-Fortin J, Coleman KA, Morrissey DE, Greenberg RA. 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. doi:, 10.1073/pnas.0807485106. Epub 2009 Feb 6. PMID:19202061 doi:http://dx.doi.org/10.1073/pnas.0807485106
- ↑ Shanbhag NM, Rafalska-Metcalf IU, Balane-Bolivar C, Janicki SM, Greenberg RA. ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks. Cell. 2010 Jun 11;141(6):970-81. doi: 10.1016/j.cell.2010.04.038. PMID:20550933 doi:10.1016/j.cell.2010.04.038
- ↑ Sy SM, Jiang J, Dong SS, Lok GT, Wu J, Cai H, Yeung ES, Huang J, Chen J, Deng Y, Huen MS. Critical roles of ring finger protein RNF8 in replication stress responses. J Biol Chem. 2011 Jun 24;286(25):22355-61. doi: 10.1074/jbc.M111.232041. Epub, 2011 May 10. PMID:21558560 doi:http://dx.doi.org/10.1074/jbc.M111.232041
- ↑ Peuscher MH, Jacobs JJ. DNA-damage response and repair activities at uncapped telomeres depend on RNF8. Nat Cell Biol. 2011 Aug 21;13(9):1139-45. doi: 10.1038/ncb2326. PMID:21857671 doi:http://dx.doi.org/10.1038/ncb2326
- ↑ Nakada S, Yonamine RM, Matsuo K. RNF8 regulates assembly of RAD51 at DNA double-strand breaks in the absence of BRCA1 and 53BP1. Cancer Res. 2012 Oct 1;72(19):4974-83. doi: 10.1158/0008-5472.CAN-12-1057. Epub, 2012 Aug 3. PMID:22865450 doi:http://dx.doi.org/10.1158/0008-5472.CAN-12-1057
- ↑ Mallette FA, Mattiroli F, Cui G, Young LC, Hendzel MJ, Mer G, Sixma TK, Richard S. RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites. EMBO J. 2012 Feb 28;31(8):1865-78. doi: 10.1038/emboj.2012.47. PMID:22373579 doi:10.1038/emboj.2012.47
- ↑ Luijsterburg MS, Acs K, Ackermann L, Wiegant WW, Bekker-Jensen S, Larsen DH, Khanna KK, van Attikum H, Mailand N, Dantuma NP. A new non-catalytic role for ubiquitin ligase RNF8 in unfolding higher-order chromatin structure. EMBO J. 2012 May 30;31(11):2511-27. doi: 10.1038/emboj.2012.104. Epub 2012 Apr, 24. PMID:22531782 doi:http://dx.doi.org/10.1038/emboj.2012.104
- ↑ Yan Z, Guo R, Paramasivam M, Shen W, Ling C, Fox D 3rd, Wang Y, Oostra AB, Kuehl J, Lee DY, Takata M, Hoatlin ME, Schindler D, Joenje H, de Winter JP, Li L, Seidman MM, Wang W. A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to the Fanconi anemia DNA repair network. Mol Cell. 2012 Jul 13;47(1):61-75. doi: 10.1016/j.molcel.2012.05.026. Epub 2012, Jun 14. PMID:22705371 doi:10.1016/j.molcel.2012.05.026
- ↑ Feng L, Chen J. The E3 ligase RNF8 regulates KU80 removal and NHEJ repair. Nat Struct Mol Biol. 2012 Jan 22;19(2):201-6. doi: 10.1038/nsmb.2211. PMID:22266820 doi:http://dx.doi.org/10.1038/nsmb.2211
- ↑ Lok GT, Sy SM, Dong SS, Ching YP, Tsao SW, Thomson TM, Huen MS. Differential regulation of RNF8-mediated Lys48- and Lys63-based poly-ubiquitylation. Nucleic Acids Res. 2012 Jan;40(1):196-205. doi: 10.1093/nar/gkr655. Epub 2011 Sep, 12. PMID:21911360 doi:http://dx.doi.org/10.1093/nar/gkr655
- ↑ Huen MS, Grant R, Manke I, Minn K, Yu X, Yaffe MB, Chen J. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell. 2007 Nov 30;131(5):901-14. Epub 2007 Nov 20. PMID:18001825 doi:10.1016/j.cell.2007.09.041
- ↑ Mattiroli F, Vissers JH, van Dijk WJ, Ikpa P, Citterio E, Vermeulen W, Marteijn JA, Sixma TK. RNF168 Ubiquitinates K13-15 on H2A/H2AX to Drive DNA Damage Signaling. Cell. 2012 Sep 14;150(6):1182-95. doi: 10.1016/j.cell.2012.08.005. PMID:22980979 doi:10.1016/j.cell.2012.08.005
- ↑ Huen MS, Grant R, Manke I, Minn K, Yu X, Yaffe MB, Chen J. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell. 2007 Nov 30;131(5):901-14. Epub 2007 Nov 20. PMID:18001825 doi:10.1016/j.cell.2007.09.041
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