RAP80, ubiquitin and SUMO in the DNA damage response

Lombardi, Patrick M.; Matunis, Michael J.; Wolberger, Cynthia

doi:10.1007/s00109-017-1561-1

Cited by 19 publications

(18 citation statements)

References 59 publications

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“…At DSB sites, such chains recruit the RAP80 scaffold protein that can preserve polyubiquitin chains as landing pads for recruitment of DNA repair proteins, such as 53BP1, that favor end joining DNA repair, and sequent recombination repair proteins, such as BRCA1 (Guzzo et al, 2012; Lombardi et al, 2017). Additionally, SUMO plays important roles in modulating multiple ubiquitin E3 functions in DSB repair (Figure 3C).…”

Section: Crosstalk Between Sumo-based and Other Signaling Processesmentioning

confidence: 99%

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

2018

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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: Crosstalk Between Sumo-based and Other Signaling Processesmentioning

confidence: 99%

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

2018

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“…An important outcome of K63-linked ubiquitylation at DSB sites is the recruitment of the DDR factors, RAP80, which has specific affinity to these ubiquitin chains due to its tandem ubiquitin-interacting motifs (Lombardi et al, 2017). Indeed, UBE4A depletion led to reduced accrual of RAP80 at DNA breaks (Figure 5A) in a manner that was dependent on UBE4A activity (Figure 5B).…”

Section: Resultsmentioning

confidence: 99%

“…Identification of the ubiquitin ligases that take part in the DDR is key to understanding ubiquitin-driven pathways in this network. Major factors in H2A ubiquitylation are the E3 ligases, RNF8 and RNF168, whose activity is required for proper recruitment of the 53BP1 protein – a platform for additional DDR proteins and a regulator of DSB repair pathway choice – and RAP80, which anchors the protein complex, BRCA1-A, whose subsequent dynamics plays a role in the critical balance between DSB repair pathways (Lombardi et al, 2017). …”

Section: Introductionmentioning

confidence: 99%

The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair

et al. 2018

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Summary Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning - the E3/E4 ubiquitin ligase, UBE4A. UBE4A’s recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end-resection at DSBs, and its abrogation leads to up-regulation of the highly mutagenic alternative end-joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning of the complex DDR network for accurate and balanced execution of DSB repair.

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“…DNA damage and centrosome amplification are critical for mammalian embryonic brain development [8,9]. To regulate DNA repair machinery, several protein posttranslational modification systems such as phosphorylation, ubiquitination, SUMOylation, and NEDDylation are involved [10]. In this chapter, to identify how DNA repair signaling pathways are involved in mammalian development and disease, ubiquitination system in DNA repair machinery are focused on and discussed.…”

Section: Introductionmentioning

confidence: 99%

Maintenance of Genome Stability by Ubiquitination of DNA Repair Proteins in Mammalian Development and Disease

Shimada¹

2018

Ubiquitination Governing DNA Repair - Implications in Health and Disease

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To maintain genome DNA, DNA repair machinery has been developed in cellular life cycle. Multiple DNA repair pathways such as base excision repair, nucleotide excision repair, DNA cross link damage repair, DNA single strand break repair and DNA double strand break repair including nonhomologous end joining and homologous recombination are regulated by protein signal cascade. Because of limited gene number, protein posttranslational modification signal has advantage to control cell dynamics during development and senescence. This chapter focuses on how DNA repair proteins molecular modification including phosphorylation and ubiquitination contribute to genome stability pathway during mammalian development and disease.

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RAP80, ubiquitin and SUMO in the DNA damage response

Cited by 19 publications

References 59 publications

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair

Maintenance of Genome Stability by Ubiquitination of DNA Repair Proteins in Mammalian Development and Disease

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