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. 2013 Jul 9:4:128.
doi: 10.3389/fgene.2013.00128. eCollection 2013.

Put a RING on it: regulation and inhibition of RNF8 and RNF168 RING finger E3 ligases at DNA damage sites

Cristina Bartocci  1 , Eros Lazzerini Denchi
Affiliations

Put a RING on it: regulation and inhibition of RNF8 and RNF168 RING finger E3 ligases at DNA damage sites

Cristina Bartocci et al. Front Genet. .

Abstract

RING (Really Interesting New Gene) domain-containing E3 ubiquitin ligases comprise a large family of enzymes that in combination with an E2 ubiquitin-conjugating enzyme, modify target proteins by attaching ubiquitin moieties. A number of RING E3s play an essential role in the cellular response to DNA damage highlighting a crucial contribution for ubiquitin-mediated signaling to the genome surveillance pathway. Among the RING E3s, RNF8 and RNF168 play a critical role in the response to double stranded breaks, one of the most deleterious types of DNA damage. These proteins act as positive regulators of the signaling cascade that initiates at DNA lesions. Inactivation of these enzymes is sufficient to severely impair the ability of cells to respond to DNA damage. Given their central role in the pathway, several layers of regulation act at this nodal signaling point. Here we will summarize current knowledge on the roles of RNF8 and RNF168 in maintaining genome integrity with particular emphasis on recent insights into the multiple layers of regulation that act on these enzymes to fine-tune the cellular response to DNA lesions.

Keywords: DNA damage response; HR; NHEJ; RING E3 ligase; RNF168; RNF8; genomic stability; ubiquitin.

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Figures

FIGURE 1
FIGURE 1
Model of RNF8/RNF168-mediated ubiquitylation at DSBs. RNF8 is recruited to DSBs through its interaction with MDC1. Chromatin-bound RNF8 cooperates with the E2 UBC13 to ubiquitylate an unknown non-nucleosomal target in the vicinity of the damaged chromatin (X). Ubiquitylated target-X is recognized by RNF168, which catalyzes monoubiquitylation of K13-15 on H2A-type histones. RNF8 and RNF168 work in concert to extend the ubiquitin chains on H2A-type histones. BRCA1 and 53BP1 are recruited as downstream effectors. BRCA1 accumulates at DSBs in an RNF8/RNF168-dependent manner, through RAP80, which binds to the K63-linked ubiquitin chains deposited by RNF8/RNF168. The RAP80–BRCA1 complex is thought to inhibit excessive HR, while BRCA1 in complex with several other DNA damage response proteins is known to primarily promote DNA repair by HR. 53BP1 accumulation at DSBs depends on RNF8/RNF168-mediated modifications to the chromatin surrounding the DNA lesion. 53BP1 promotes DNA repair by NHEJ (Me, methylation of H4K20).
FIGURE 2
FIGURE 2
Chromatin decondensation at DSBs. The chromatin remodeling factors p400 and CHD4 mediate large-scale chromatin decondensation at DSB sites, promoting RNF8/RNF168-mediated ubiquitylation and other chromatin modifications. P400 is recruited by MDC1, CHD4 by RNF8. SMARCA5 is recruited through RNF168 and promotes its activity at DSBs.
FIGURE 3
FIGURE 3
Modulation of RNF8/RNF168 signaling through de-ubiquitylation. Different DUBs act at different levels of the RNF8/RNF168 cascade to inhibit, modulate, or turn off the ubiquitin signal generated by the two E3s. USP3 de-ubiquitylates RNF8 targets; OTUB1 acts on substrates of RNF168, and BRCC36 acts downstream, severing ubiquitin chains generated presumably by both E3s (and possibly also on BRCA1 targets, indicated by the dashed arrow).
FIGURE 4
FIGURE 4
TRIP12 and UBR5-mediated suppression of DSB-induced chromatin ubiquitylation. The HECT E3 ligases TRIP12 and UBR5 control the nuclear pool of RNF168 (top). If TRIP12 and UBR5 are depleted, hyper-accumulation of RNF168 triggers excessive spreading of ubiquitylated H2A/H2AX far away from the initial site of DNA lesion (bottom).
FIGURE 5
FIGURE 5
RNF168 inhibition at chromosome ends. TRF2 protects telomeres from unwanted activation of a DDR both by preventing upstream ATM activation and by inhibiting RNF168 ubiquitylation at these sites through recruitment of UBR5 and BRCC36.
FIGURE 6
FIGURE 6
Possible role of PcG proteins in the DDR. BMI1/RING1B are recruited to DSBs, where they are thought to mediate the transcriptional silencing observed at DSBs via deposition of the K119 mark on H2A-type histones. RNF8/RNF168 also may contribute to gene repression at DSBs. BMI1/RING1B may also play additional roles in DDR signaling which remain to be uncovered.
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