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E3 ubiquitin-protein ligase RNF168

Definition:

E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the RNF8-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of '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. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).

References:

[1]. Francesca Mattiroli, et al. RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell. 2012 Sep 14;150(6):1182-95. [Content Brief]

[2]. Amélie Fradet-Turcotte, et al. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature. 2013 Jul 4;499(7456):50-4. [Content Brief]

[3]. Niraj M Shanbhag, et al. ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks. Cell. 2010 Jun 11;141(6):970-81. [Content Brief]

[4]. Grant S Stewart, et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell. 2009 Feb 6;136(3):420-34. [Content Brief]

[5]. Marco Gatti, et al. A novel ubiquitin mark at the N-terminal tail of histone H2As targeted by RNF168 ubiquitin ligase. Cell Cycle. 2012 Jul 1;11(13):2538-44. [Content Brief]

[6]. Carsten Doil, et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell. 2009 Feb 6;136(3):435-46. [Content Brief]

[7]. Stephanie Panier, et al. Tandem protein interaction modules organize the ubiquitin-dependent response to DNA double-strand breaks. Mol Cell. 2012 Aug 10;47(3):383-95. [Content Brief]

[8]. Frédérick A Mallette, et al. RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites. EMBO J. 2012 Apr 18;31(8):1865-78. [Content Brief]

[9]. Zhijiang Yan, et al. 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. [Content Brief]

[10]. Karine Jacquet, et al. The TIP60 Complex Regulates Bivalent Chromatin Recognition by 53BP1 through Direct H4K20me Binding and H2AK15 Acetylation. Mol Cell. 2016 May 5;62(3):409-421. [Content Brief]

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