Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers

Schwertman, Petra; Bekker‐Jensen, Simon; Mailand, Niels

doi:10.1038/nrm.2016.58

Cited by 318 publications

(292 citation statements)

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“…Such a role could effectively modulate multiple forms of DNA transaction within these structures. In addition, SUMO is well known to regulate individual DNA transaction, such as transcription and DNA repair, by directly targeting proteins involved in these processes; as these topics have been extensively reviewed, we refer readers to some of these articles for details (Rosonina et al, 2017; Sarangi and Zhao, 2015; Schwertman et al, 2016; Wei and Zhao, 2017). …”

Section: Sumo Modulates Chromosome Structures and Functionsmentioning

confidence: 99%

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

Zhao

2018

Molecular Cell

196

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Summary Since the discovery of SUMO twenty years ago, SUMO conjugation has become a widely-recognized post-translational modification that targets a myriad of proteins in many processes. Great progress has been made in understanding the SUMO pathway enzymes, substrate sumoylation, and the interplay between sumoylation and other regulatory mechanisms in a variety of contexts. As these research directions continue to generate insights into SUMO-based regulation, several mechanisms by which sumoylation and desumoylation can orchestrate large biological effects are emerging. These include the ability to target multiple proteins within the same cellular structure or process, respond dynamically to external and internal stimuli, and modulate signaling pathways involving other post-translational modifications. Focusing on nuclear function and intracellular signaling, this review highlights a broad spectrum of historical data and recent advances with the aim of providing an overview of mechanisms underlying SUMO-mediated global effects to stimulate further inquiry into intriguing roles of SUMO.

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Section: Sumo Modulates Chromosome Structures and Functionsmentioning

confidence: 99%

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

Zhao

2018

Molecular Cell

196

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“…Ubiquitin transfer is facilitated by the coordinate action of 3 different types of enzymes, E1 for activation, E2 for conjugation, and E3 for ligation (11). The monoubiquitination of FANCD2 and FANCI by the E3 ligase FANCL and the E2 ligase UBE2T (also known as FANCT) are key steps of the FA/BRCA pathway (7). Compromised function of FANCD2, FANCI, FANCL, or FANCT due to defective ubiquitin transfer can abrogate the FA/BRCA pathway (9).…”

Section: Introductionmentioning

confidence: 99%

“…Ubiquitination has become an important issue of ICL repair, including ubiquitin donors and acceptors (7). Ubiquitin transfer is facilitated by the coordinate action of 3 different types of enzymes, E1 for activation, E2 for conjugation, and E3 for ligation (11).…”

Section: Introductionmentioning

confidence: 99%

“…Other frequent aspects of FA comprise early-onset bone marrow failure and cancer predisposition, specifically for acute myelogenous leukemia and head and neck squamous cell carcinoma (1)(2)(3)(4). FA results from faults in the FA/BRCA pathway for DNA interstrand cross-link (ICL) repair, in which proteins encoded by 21 FA genes reported thus far -designated as or aliased with the prefix FANC-and serial letters of the alphabet, FANCA to FANCV -and associated proteins interact (5)(6)(7)(8)(9). Germline inactivation of any one of the FA genes causes classical FA or variant (FA-like) disease lacking single clinical core features of FA.…”

Section: Introductionmentioning

confidence: 99%

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Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Knies¹,

Inano²,

Ramı́rez³

et al. 2017

Journal of Clinical Investigation

177

171

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The WD40-containing E3 ubiquitin ligase RFWD3 has been recently linked to the repair of DNA damage by homologous recombination (HR). Here we have shown that an RFWD3 mutation within the WD40 domain is connected to the genetic disease Fanconi anemia (FA). An individual presented with congenital abnormalities characteristic of FA. Cells from the patient carrying the compound heterozygous mutations c.205_206dupCC and c.1916T>A in RFWD3 showed increased sensitivity to DNA interstrand cross-linking agents in terms of increased chromosomal breakage, reduced survival, and cell cycle arrest in G 2 phase. The cellular phenotype was mirrored in genetically engineered human and avian cells by inactivation of RFWD3 or introduction of the patient-derived missense mutation, and the phenotype was rescued by expression of wild-type RFWD3 protein. HR was disrupted in RFWD3-mutant cells as a result of impaired relocation of mutant RFWD3 to chromatin and defective physical interaction with replication protein A. Rfwd3 knockout mice appear to have increased embryonic lethality, are subfertile, show ovarian and testicular atrophy, and have a reduced lifespan resembling that of other FA mouse models. Although RFWD3 mutations have thus far been detected in a single child with FA, we propose RFWD3 as an FA gene, FANCW, supported by cellular paradigm systems and an animal model.

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“…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)(5)(6)(7)(8)(9)(10)(11).…”

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confidence: 99%

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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Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers

Cited by 318 publications

References 171 publications

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Dual-utility NLS drives RNF169-dependent DNA damage responses

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