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Ubiquitin and SUMO in DNA Repair at a Glance

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Ubiquitin and SUMO in DNA Repair at a Glance Cell Science at a Glance 249 Ubiquitin and SUMO in The task of preserving the stability of the genetic synthesis makes them ideal regulators for fine- information of a cell is characterised by several tuning DNA repair and damage response DNA repair at a glance important requirements (Hoeijmakers, 2009). pathways. Their general action as modulators of First, genome maintenance is a largely cell- protein function goes far beyond their Helle D. Ulrich autonomous function, as each cell within an contribution to regulated proteolysis, for which organism is obliged to prevent or repair injury of ubiquitin first became famous (Glickman and Cancer Research UK London Research Institute, its own genome. Second, insults that endanger Clare Hall Laboratories, Blanche Lane, South Ciechanover, 2002). Mimms, Hertfordshire EN6 3LD, UK genome stability require a rapid response In this Cell Science at a Glance article and the [email protected] because damage to the genetic material quickly accompanying poster, I will summarise the affects essential cellular functions by interfering Journal of Cell Science 125, 249–254 contributions of ubiquitin and SUMO to the © 2012. Published by The Company of Biologists Ltd with gene expression. Third, any response needs major pathways of genome maintenance. doi:10.1242/jcs.091801 to be reversibly tuned to the physiological state Several excellent reviews on this topic have of the cell, in particular its stage within the cell This article is part of a Minifocus on Ubiquitin. For been published over the past years, which give further reading, please see related articles: ʻEmerging cycle. Last, but not least, mechanisms for the insight into the relevant mechanisms involved regulatory mechanisms in ubiquitin-dependent cell protection of genome integrity have to react (Al-Hakim et al., 2010; Bergink and Jentsch, cycle controlʼ by Annamaria Mocciaro and Michael flexibly to a large variety of damaging agents to Rape (J. Cell Sci. 125, 255-263). ʻThe role of which a cell may be exposed. 2009; Huang and D’Andrea, 2006; Ulrich and ubiquitylation in receptor endocytosis and endosomal Walden, 2010). Here, I will place more sortingʼ by Kaisa Haglund and Ivan Dikic (J. Cell Sci. Considering these characteristics of DNA 125, 265-275). ʻCellular functions of the DUBsʼ by repair, it is not surprising that post-translational emphasis on the crosstalk between individual Michael J. Clague et al. (J. Cell Sci. 125, 277-286). modifications with members of the ubiquitin repair pathways and the specific contributions of ʻHECT and RING finger families of E3 ubiquitin selected proteins involved in ubiquitin and ligases at a glanceʼ by Meredith B. Metzger et al. (J. family, such as ubiquitin itself and small Cell Sci. 125, 531-537). ʻNon-canonical ubiquitin- ubiquitin-related modifier (SUMO), have been SUMO conjugation to the processes involved. based signals for proteasomal degradationʼ by Yelena identified as key contributors to genome For information about the general principles of Kravtsova-Ivantsiv and Aaron Ciechanover (J. Cell maintenance. The notion that ubiquitin and protein ubiquitylation and SUMOylation, the Sci. 125, 539-548). ʻNo one can whistle a symphony SUMO can rapidly and reversibly change the reader is referred to pertinent reviews in this alone – how different ubiquitin linkages cooperate to orchestrate NF-B activityʼ by Anna C. Schmukle and properties, stability or localisation of their target field (Glickman and Ciechanover, 2002; Henning Walczak (J. Cell Sci. 125, 549-559). proteins without the need for de novo protein Kerscher et al., 2006). Journal of Cell Science (See poster insert) 250 Journal of Cell Science 125 (2) The response to DNA double-strand domains (Doil et al., 2009; Stewart et al., 2009). BRCA1/BRCA2-containing complex, subunit breaks RNF168, together with UBC13, catalyses the 3), ubiquitin specific peptidases (USP) 3 and 16 DNA double-strand breaks (DSBs) represent formation of polymeric chains, linked through as well as OTUB1 (for OTU domain, ubiquitin perhaps the most dangerous type of DNA lesion lysine (K) 63 of ubiquitin, that in turn recruit the aldehyde binding 1). BRCC36 is part of the because they have dramatic effects on all DNA adapter protein RAP80 (receptor associated RAP80 complex and exhibits a preference for transactions, including proper segregation of protein 80, also known as UIMC1) through its K63-polyubiquitin chains (Sobhian et al., 2007). chromosomes during cell division ubiquitin-interacting motifs (UIM). The dimeric USP3 and USP16 have both been shown to act (Hoeijmakers, 2009). In order to initiate repair, a BRCA1–BARD1 complex is eventually on histone H2A and seem to downregulate the series of phosphorylation events, namely the recruited through the interaction of the BRCA1 pathway at the stage of RNF8 (Cai et al., 1999; phosphorylation of the histone variant H2AX tandem BRCT motifs with the phosphorylated Doil et al., 2009; Joo et al., 2007; Nicassio et al., and mediator of DNA-damage checkpoint 1 abraxas protein (also known as FAM175A), 2007), whereas OTUB1 acts further (MDC1) by the checkpoint kinase ataxia which is itself part of a multisubunit scaffold downstream and might inhibit the action of telangiectasia mutated (ATM), leads to the complex (Kim et al., 2007; Liu et al., 2007; UBC13 in a non-catalytic manner (Nakada sequential recruitment of several E3 ubiquitin Sobhian et al., 2007; Wang et al., 2007). et al., 2010). The negative influence of DUBs on ligases in higher eukaryotes, as detailed below Although it is clear that BRCA1 is an important the formation of damage-induced BRCA1 and (Bekker-Jensen and Mailand, 2011; Panier and mediator of DNA DSB repair through TP53BP1 foci indicates that cells maintain a fine Durocher, 2009; Tang and Greenberg, 2010). homologous recombination, its relevant balance between ubiquitylation and deubiquity- These enzymes promote extensive substrate proteins and cognate E2 enzyme(s), lation to regulate DSB repair. ubiquitylation of histone H2A and other, yet the structure of the resulting ubiquitin In addition to ubiquitylation, the post- unknown, chromatin-associated proteins in a conjugates and the physiological consequences translational modifications at DSBs also involve cascade that eventually results in the localisation of these modifications are not yet fully SUMOylation, which is mediated by the SUMO of another RING-finger ubiquitin ligase, understood (Hiom, 2010). E3 PIAS1 and PIAS4 proteins (for protein BRCA1 (for breast cancer 1, early onset), as In addition to BRCA1, several other ubiquitin inhibitor of activated STAT), which both well as the checkpoint protein TP53BP1 (for E3s participate in the cascade, although their associate with the single SUMO E2 UBC9 (also tumor protein p53 binding protein 1), to the roles are less well defined. On one hand, known as UBE2I) (Galanty et al., 2009; Morris break. Whereas BRCA1 is essential for RAD18, a RING-finger E3 best known for its et al., 2009). One of the substrates appears to be initiating DSB repair by homologous function in DNA damage bypass (see below), BRCA1 itself, whose catalytic activity is recombination, TP53BP1 has been associated acts downstream of RNF8, presumably by being boosted by SUMO modification. Hence, with repair by non-homologous end-joining recruited to chromatin by means of a ubiquitin- SUMOylation of the ubiquitin E3 BRCA1 (Hiom, 2010). binding zinc finger (UBZ) domain (Huang et al., represents an interesting example of crosstalk The mechanistic details of TP53BP1 2009). Intriguingly, the binding of RAD18, but between the two modifiers. In addition, the recruitment to DSBs are poorly understood. The not its E3 ligase activity, is required for proper polycomb protein Pc2 (officially known as protein binds to methylated histones, and it is homologous recombination. On the other hand, CBX4), which acts as a SUMO ligase on a unclear how the damage-induced ubiquitylation HERC2, a large HECT domain family E3 number of substrates, including itself (Wotton Journal of Cell Science cascade elicits this signal for chromatin protein, associates with the FHA domain of and Merrill, 2007), is also recruited to chromatin association of TP53BP1. By contrast, the RNF8 and seems to promote interaction with in a damage-dependent manner (Chou et al., signalling pathway leading to BRCA1 UBC13 in an as yet unknown way (Bekker- 2010). There are clearly additional physiologi- recruitment has now been roughly elucidated. Jensen et al., 2010). Finally, a number of cally relevant targets, whose SUMOylation is Although there are indications that the pathway polycomb group proteins, which mediate important during DSB repair, but these remain is not entirely linear, the prevailing concept is transcriptional repression through modulation to be identified. based on the recognition of post-translational of chromatin structure, have recently been Apart from the direct involvement in the modifications, such as phosphate or ubiquitin shown to contribute to the recruitment of both recruitment of repair factors, histone moieties, by dedicated domains in the respective BRCA1 and TP53BP1 through H2A and H2AX ubiquitylation is known to affect chromatin on a effector proteins, which themselves trigger the ubiquitylation (Gieni et al., 2011). These include structural level, which is particularly important recruitment of additional enzymes for the RING-finger proteins BMI1 and RNF2 (also for the activation of transcription. In higher modification of other chromatin components.
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