RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling.

By Francesca Mattiroli, J. Vissers, W. Dijk, Pauline T. Ikpa, E. Citterio, W. Vermeulen, J. Marteijn, T. Sixma. Cell, 2012

649 citations recorded by the source corpus.

Ubiquitin-dependent signaling during the DNA damage response (DDR) to double-strand breaks (DSBs) is initiated by two E3 ligases, RNF8 and RNF168, targeting histone H2A and H2AX. RNF8 is the first ligase recruited to the damage site, and RNF168 follows RNF8-dependent ubiquitination. This suggests that RNF8 initiates H2A/H2AX ubiquitination with K63-linked ubiquitin chains and RNF168 extends them. Here, we show that RNF8 is inactive toward nucleosomal H2A, whereas RNF168 catalyzes the monoubiquitination of the histones specifically on K13-15. Structure-based mutagenesis of RNF8 and RNF168 RING domains shows that a charged residue determines whether nucleosomal proteins are recognized. We find that K63 ubiquitin chains are conjugated to RNF168-dependent H2A/H2AX monoubiquitination at K13-15 and not on K118-119. Using a mutant of RNF168 unable to target histones but still catalyzing ubiquitin chains at DSBs, we show that ubiquitin chains per se are insufficient for signaling, but RNF168 target ubiquitination is required for DDR.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/8ea7af067bb5d6cc0ea6e5cc32860236aa392dbd

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In Molecular Biology

1. Stephen P. Jackson
2. Andrew N. Blackford
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In Oncology

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2. Alexandre Maréchal
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Citations in the corpus

• 53BP1 is a reader of the DNA damage-induced H2A Lys15 ubiquitin mark (2013, positive): “RNF168wasrecentlyshowntocatalyseanewhistonemark, H2AK13/K15monoubiquitination(H2AK13/K15ub) 26,27 ,andthus we sought to test whether 53BP1 could potentially bind to nucleosomes containing RNF168-ubiquitinated H2A.”
• DNA damage sensing by the ATM and ATR kinases. (2013, background): “3B) (Huen et al. 2007; Kim et al. 2007a,b; Kolas et al. 2007; Mailand et al. 2007; Sobhian et al. 2007; Wang and Elledge 2007; Wang et al. 2007; Doil et al. 2009; Galanty et al. 2009; Morris et al. 2009; Stewart 2009; Bekker-Jensen et al. 2010; Meerang et al. 2011; Mattiroli et al. 2012).”
• ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. (2017, background): “, 2005), although there is some dispute as to whether T2609 may also be phosphorylated by ATM and ATR in certain circumstances (Chen et al., 2007; Jiang et al., 2015; Meek et al., 2007; Yajima et al., 2006).”