Reactome | RNF8 and RNF168 ubiquitinate H2AFX

RNF8 and RNF168 ubiquitinate H2AFX

Stable Identifier

R-HSA-5682858

Type

Reaction [transition]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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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
18001825	RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly Minn, K, Huen, MS, Manke, I, Grant, R, Chen, J, Yu, X, Yaffe, MB	Cell	2007
22589545	Molecular insights into the function of RING finger (RNF)-containing proteins hRNF8 and hRNF168 in Ubc13/Mms2-dependent ubiquitylation Campbell, SJ, Neculai, D, Leung, CC, Glover, JN, Dhe-Paganon, S, Hodge, CD, Edwards, RA	J. Biol. Chem.	2012
18001824	RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins Lukas, J, Faustrup, H, Bartek, J, Melander, F, Lukas, C, Bekker-Jensen, S, Mailand, N	Cell	2007
19203578	The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage Townsend, K, Al-Hakim, AK, Stankovic, T, Taylor, AM, Byrd, PJ, Stewart, GS, Pelletier, L, Oldreive, C, Olivarius, S, Taubenheim, N, Durocher, D, Panier, S, Mendez, M, Wildenhain, J, Nakada, S, Kolas, NK, Miller, ES, Tagliaferro, A, Durandy, A, Ylanko, J	Cell	2009
22980979	RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling Sixma, TK, Marteijn, JA, Vissers, JH, Citterio, E, Ikpa, P, Mattiroli, F, van Dijk, WJ, Vermeulen, W	Cell	2012
19203579	RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins Durocher, D, Panier, S, Doil, C, Larsen, DH, Lukas, J, Menard, P, Bartek, J, Pepperkok, R, Lukas, C, Ellenberg, J, Bekker-Jensen, S, Mailand, N	Cell	2009

Participants

Input

Output

DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,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] (Homo sapiens)

Participates

as an event of

Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (Homo sapiens)

Catalyst Activity

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]

Physical Entity

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] (Homo sapiens)

Activity

ubiquitin protein ligase activity (GO:0061630)

Orthologous Events

RNF8 and RNF168 ubiquitinate H2AFX (Bos taurus)

RNF8 and RNF168 ubiquitinate H2AFX (Canis familiaris)

RNF8 and RNF168 ubiquitinate H2AFX (Drosophila melanogaster)

RNF8 and RNF168 ubiquitinate H2AFX (Gallus gallus)

RNF8 and RNF168 ubiquitinate H2AFX (Mus musculus)

RNF8 and RNF168 ubiquitinate H2AFX (Rattus norvegicus)

RNF8 and RNF168 ubiquitinate H2AFX (Saccharomyces cerevisiae)