Ring Finger Protein RNF169 Antagonizes the Ubiquitin-dependent Signaling Cascade at Sites of DNA Damage

Chen, Jie; Feng, Wei; Jiang, Jun; Deng, Yiqun; Huen, Michael S.Y.

doi:10.1074/jbc.m112.373530

Cited by 65 publications

(94 citation statements)

References 31 publications

(50 reference statements)

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“…Recently RNF169 has also been identified as an UBDcontaining protein that competes with or interferes with 53BP1 localization within IRIF and negatively regulates the DDR. [30][31][32] However, we do not believe endogenous RAD18 plays a large role in negatively regulating chromatin spreading of DDR factors. This is based on our inability to detect altered DNA repair in cells depleted of RAD18 using siRNA approaches.…”

Section: Ectopic Expression Of Rad18 Inhibits Recruitment Of 53bp1 Bmentioning

confidence: 99%

A small ubiquitin binding domain inhibits ubiquitin-dependent protein recruitment to DNA repair foci

et al. 2013

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Section: Ectopic Expression Of Rad18 Inhibits Recruitment Of 53bp1 Bmentioning

confidence: 99%

A small ubiquitin binding domain inhibits ubiquitin-dependent protein recruitment to DNA repair foci

et al. 2013

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“…Next, it has been demonstrated that RNF169, an E3 ubiquitin ligase paralogous to RNF168, accumulates at DNA damage foci through direct recognition of RNF168-mediated histone ubiquitylation. Therefore, RNF169 functionally competes with 53BP1 for association with ubiquitinated histones, and impairs the 53BP1 recruitment at sites of DNA damage, resulting in stimulated HR and restrained NHEJ (Chen et al, 2012;Poulsen et al, 2012). Moreover, p400 SWI/SNF ATPase and HERC2 are required for RNF8/RNF168-mediated ubiquitination, either by destabilization of nucleosomes or by facilitating the assembly of the ubiquitin-conjugating enzyme Ubc13 with RNF8 (Bekker-Jensen et al, 2010;Xu et al, 2010).…”

Section: Ubiquitinationmentioning

confidence: 99%

Histone modifications in DNA damage response

Cao

Shen

Zhu

2016

Sci. China Life Sci.

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DNA damage is a relatively common event in eukaryotic cell and may lead to genetic mutation and even cancer. DNA damage induces cellular responses that enable the cell either to repair the damaged DNA or cope with the damage in an appropriate way. Histone proteins are also the fundamental building blocks of eukaryotic chromatin besides DNA, and many types of post-translational modifications often occur on tails of histones. Although the function of these modifications has remained elusive, there is ever-growing studies suggest that histone modifications play vital roles in several chromatin-based processes, such as DNA damage response. In this review, we will discuss the main histone modifications, and their functions in DNA damage response.DNA damage response, histone modifications, chromatin, DNA repair Citation:

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“…To understand the regulatory basis for the USP7-RNF169 interaction better, we further mapped the USP7-binding domain on the RNF169 polypeptide. In addition to the previously characterized RNF169 mutants (20), we generated a series of RNF169 deletion mutants (Fig. 1D) and analyzed their ability to interact with USP7 (Fig.…”

Section: Significancementioning

confidence: 99%

“…In stark contrast to RNF168, which plays positive roles in amplifying ubiquitin-dependent DSB signals (18,19), RNF169 is endowed with antagonistic properties in the DSB signal transduction pathway. Indeed, RNF169 competes for RNF168-catalyzed ubiquitin adducts and displaces 53BP1 and RAP80 from DSBs (14,20,21). Despite its putative role as an integral component of the DSB signal transduction cascade, how RNF169 is regulated mechanistically and how it contributes to the multipartite self-restraining mechanisms in DNA damage surveillance and repair processes remain to be established.…”

mentioning

confidence: 99%

“…As part of our effort in probing the self-restraining mechanisms of DSB signal transduction, we analyzed the RNF169 interactome. Although RNF169 limits excessive loading of the DNA damage-mediator proteins 53BP1 and RAP80 at DSBs (14,20,21), exactly how its activity is regulated is not known. To this end, we affinity-purified RNF169 protein complexes from 293T cells engineered to express S protein-Flag-Streptavidin-binding peptide (SFB)-tagged RNF169 stably.…”

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confidence: 99%

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Dual-utility NLS drives RNF169-dependent DNA damage responses

Jiang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Loading of p53-binding protein 1 (53BP1) and receptor-associated protein 80 (RAP80) at DNA double-strand breaks (DSBs) drives cell cycle checkpoint activation but is counterproductive to high-fidelity DNA repair. ring finger protein 169 (RNF169) maintains the balance by limiting the deposition of DNA damage mediator proteins at the damaged chromatin. We report here that this attribute is accomplished, in part, by a predicted nuclear localization signal (NLS) that not only shuttles RNF169 into the nucleus but also promotes its stability by mediating a direct interaction with the ubiquitin-specific protease USP7. Guided by the crystal structure of USP7 in complex with the RNF169 NLS, we uncoupled USP7 binding from its nuclear import function and showed that perturbing the USP7-RNF169 complex destabilized RNF169, compromised high-fidelity DSB repair, and hypersensitized cells to poly (ADP-ribose) polymerase inhibition. Finally, expression of USP7 and RNF169 positively correlated in breast cancer specimens. Collectively, our findings uncover an NLS-mediated bipartite mechanism that supports the nuclear function of a DSB response protein.ells respond to DNA double-strand breaks (DSBs) by mounting a series of signal transduction events that culminate in cell arrest and DNA repair (1). Signal transduction entails the coordinated assembly of a cohort of DNA damage mediator proteins, including p53-binding protein 1 (53BP1) and receptor-associated protein 80 (RAP80), at the damaged chromatin, which, in turn, enforces checkpoint control and cell tolerance to DNA damage (2, 3). Paradoxically, although DSB loading of 53BP1 and RAP80 underlies robust activation of DNA damage responses (DDRs), they operate at the expense of high-fidelity DNA repair, because their productive accumulation at DSB-flanking chromatin blocks DNA end resection and suppresses RAD51-dependent homologous recombination (HR) repair (4-11). Exactly how cells achieve a balance between robust DSB signal transduction and HR repair remains to be defined, but several lines of evidence converge on the idea that limiting the extent of DSB ubiquitylation may selectively promote HR repair (12-15), highlighting the need for cell-intrinsic mechanisms to restrain chromatin responses arising from DSBs (16).Intriguingly, one such cell-intrinsic strategy involves ring finger protein 169 (RNF169), a paralog of the RIDDLE (radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties) syndrome protein RNF168 (17,18). In stark contrast to RNF168, which plays positive roles in amplifying ubiquitin-dependent DSB signals (18,19), RNF169 is endowed with antagonistic properties in the DSB signal transduction pathway. Indeed, RNF169 competes for RNF168-catalyzed ubiquitin adducts and displaces 53BP1 and RAP80 from DSBs (14,20,21). Despite its putative role as an integral component of the DSB signal transduction cascade, how RNF169 is regulated mechanistically and how it contributes to the multipartite self-restraining mechanisms in DNA damage surveillance and...

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Ring Finger Protein RNF169 Antagonizes the Ubiquitin-dependent Signaling Cascade at Sites of DNA Damage

Cited by 65 publications

References 31 publications

A small ubiquitin binding domain inhibits ubiquitin-dependent protein recruitment to DNA repair foci

A small ubiquitin binding domain inhibits ubiquitin-dependent protein recruitment to DNA repair foci

Histone modifications in DNA damage response

Dual-utility NLS drives RNF169-dependent DNA damage responses

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