RNF8 and RNF168 ubiquitinate H2AFX

Stable Identifier
R-HSA-5682858
Type
Reaction [transition]
Species
Homo sapiens
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RNF8 and RNF168 E3 ubiquitin ligases work in concert with the E2 ubiquitin ligase complex UBE2N:UBE2V2 (UBC13:MMS2) to polyubiquitinate histone H2AFX (H2AX) on lysine residues K14 and K16 (commonly labeled in literature as K13 and K15) via ubiquitin lysine K63-directed cross-linking (Mattiroli et al. 2012). The scenario best supported by experimental evidence is that RNF8 initiates ubiquitination of H2AFX, followed by RNF168 binding to and extending ubiquitin chains ligated by RNF8 (Huen et al. 2007, Mailand et al. 2007, Stewart et al. 2009, Doil et al. 2009, Campbell et al. 2012).

Literature References
PubMed ID Title Journal Year
22589545 Molecular insights into the function of RING finger (RNF)-containing proteins hRNF8 and hRNF168 in Ubc13/Mms2-dependent ubiquitylation

Campbell, SJ, Edwards, RA, Leung, CC, Neculai, D, Hodge, CD, Dhe-Paganon, S, Glover, JN

J. Biol. Chem. 2012
18001825 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
18001824 RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins

Mailand, N, Bekker-Jensen, S, Faustrup, H, Melander, F, Bartek, J, Lukas, C, Lukas, J

Cell 2007
19203578 The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage

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

Cell 2009
22980979 RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling

Mattiroli, F, Vissers, JH, van Dijk, WJ, Ikpa, P, Citterio, E, Vermeulen, W, Marteijn, JA, Sixma, TK

Cell 2012
19203579 RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins

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

Cell 2009
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Catalyst Activity
Title
ubiquitin protein ligase activity of DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4 [nucleoplasm]
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