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      Ubiquitylation, neddylation and the DNA damage response

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      Author(s): ,
      Publication date (Electronic):
      Journal: Open Biology
      Publisher: The Royal Society
      Keywords: DNA damage response, double-strand break repair, ubiquitin, NEDD8, MLN4924

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          Abstract

          Failure of accurate DNA damage sensing and repair mechanisms manifests as a variety of human diseases, including neurodegenerative disorders, immunodeficiency, infertility and cancer. The accuracy and efficiency of DNA damage detection and repair, collectively termed the DNA damage response (DDR), requires the recruitment and subsequent post-translational modification (PTM) of a complex network of proteins. Ubiquitin and the ubiquitin-like protein (UBL) SUMO have established roles in regulating the cellular response to DNA double-strand breaks (DSBs). A role for other UBLs, such as NEDD8, is also now emerging. This article provides an overview of the DDR, discusses our current understanding of the process and function of PTM by ubiquitin and NEDD8, and reviews the literature surrounding the role of ubiquitylation and neddylation in DNA repair processes, focusing particularly on DNA DSB repair.

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          RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO.

          Carsten Hoege, Boris Pfander, George-Lucian Moldovan … (2002)
          The RAD6 pathway is central to post-replicative DNA repair in eukaryotic cells; however, the machinery and its regulation remain poorly understood. Two principal elements of this pathway are the ubiquitin-conjugating enzymes RAD6 and the MMS2-UBC13 heterodimer, which are recruited to chromatin by the RING-finger proteins RAD18 and RAD5, respectively. Here we show that UBC9, a small ubiquitin-related modifier (SUMO)-conjugating enzyme, is also affiliated with this pathway and that proliferating cell nuclear antigen (PCNA) -- a DNA-polymerase sliding clamp involved in DNA synthesis and repair -- is a substrate. PCNA is mono-ubiquitinated through RAD6 and RAD18, modified by lysine-63-linked multi-ubiquitination--which additionally requires MMS2, UBC13 and RAD5--and is conjugated to SUMO by UBC9. All three modifications affect the same lysine residue of PCNA, suggesting that they label PCNA for alternative functions. We demonstrate that these modifications differentially affect resistance to DNA damage, and that damage-induced PCNA ubiquitination is elementary for DNA repair and occurs at the same conserved residue in yeast and humans.
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            Recognition and processing of ubiquitin-protein conjugates by the proteasome.

            Daniel Finley (2009)
            The proteasome is an intricate molecular machine, which serves to degrade proteins following their conjugation to ubiquitin. Substrates dock onto the proteasome at its 19-subunit regulatory particle via a diverse set of ubiquitin receptors and are then translocated into an internal chamber within the 28-subunit proteolytic core particle (CP), where they are hydrolyzed. Substrate is threaded into the CP through a narrow gated channel, and thus translocation requires unfolding of the substrate. Six distinct ATPases in the regulatory particle appear to form a ring complex and to drive unfolding as well as translocation. ATP-dependent, degradation-coupled deubiquitination of the substrate is required both for efficient substrate degradation and for preventing the degradation of the ubiquitin tag. However, the proteasome also contains deubiquitinating enzymes (DUBs) that can remove ubiquitin before substrate degradation initiates, thus allowing some substrates to dissociate from the proteasome and escape degradation. Here we examine the key elements of this molecular machine and how they cooperate in the processing of proteolytic substrates.
            Article 0 comments Cited 499 times – based on 0 reviews     Review now
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              Human CtIP promotes DNA end resection.

              Alessandro Sartori, Claudia Lukas, Julia Coates … (2007)
              In the S and G2 phases of the cell cycle, DNA double-strand breaks (DSBs) are processed into single-stranded DNA, triggering ATR-dependent checkpoint signalling and DSB repair by homologous recombination. Previous work has implicated the MRE11 complex in such DSB-processing events. Here, we show that the human CtIP (RBBP8) protein confers resistance to DSB-inducing agents and is recruited to DSBs exclusively in the S and G2 cell-cycle phases. Moreover, we reveal that CtIP is required for DSB resection, and thereby for recruitment of replication protein A (RPA) and the protein kinase ATR to DSBs, and for the ensuing ATR activation. Furthermore, we establish that CtIP physically and functionally interacts with the MRE11 complex, and that both CtIP and MRE11 are required for efficient homologous recombination. Finally, we reveal that CtIP has sequence homology with Sae2, which is involved in MRE11-dependent DSB processing in yeast. These findings establish evolutionarily conserved roles for CtIP-like proteins in controlling DSB resection, checkpoint signalling and homologous recombination.
              Article 0 comments Cited 467 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Open Biol
                Journal ID (iso-abbrev): Open Biol
                Journal ID (publisher-id): RSOB
                Journal ID (hwp): royopenbio
                Title: Open Biology
                Publisher: The Royal Society
                ISSN (Electronic): 2046-2441
                Publication date Collection: April 2015
                Publication date (Electronic): 1 April 2015
                Publication date PMC-release: 1 April 2015
                Volume: 5
                Issue: 4
                Electronic Location Identifier: 150018
                Affiliations
                The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge , Cambridge CB2 1QN, UK
                Author notes
                Article
                Publisher ID: rsob150018
                DOI: 10.1098/rsob.150018
                PMC ID: 4422126
                PubMed ID: 25833379
                SO-VID: a7d5bd17-81b1-446a-980d-920ebccd0669
                Copyright ©
                License:

                © 2015 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

                History
                Date received : 28 January 2015
                Date accepted : 9 March 2015
                Categories
                Subject: 1001
                Subject: 33
                Subject: 129
                Subject: Review
                Subject: Review Article
                Custom metadata
                cover-date April 2015

                ScienceOpen disciplines: Life sciences
                Keywords: dna damage response,double-strand break repair,ubiquitin,nedd8,mln4924
                Data availability:
                ScienceOpen disciplines: Life sciences
                Keywords: dna damage response, double-strand break repair, ubiquitin, nedd8, mln4924

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