Nuclear organization in genome stability: SUMO connections

Nagai, Shoichi; Davoodi, Niloofar; Gasser, Susan M.

doi:10.1038/cr.2011.31

Cited by 83 publications

(78 citation statements)

References 100 publications

(204 reference statements)

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“…Slx5 and Slx8 function as heterodimers that bind SUMO through one SIM and ubiquitinate the substrate through the RING domain of Slx8. Although the identity of the SUMO-modified substrates has not been established, depletion of either Slx5 or Slx8 leads to accumulation of sumoylated proteins (44), and these STUBLs are required for genome stability in yeast (21). In mammals, over 200 RING-containing proteins have been reported, but the only STUBL characterized so far is RNF4, which contains four SIMs that generate preferential binding to poly-SUMO chains, suggesting that in mammals, STUBLs specifically target poly-SUMOmodified substrates for degradation (9).…”

Section: Discussionmentioning

confidence: 99%

Arkadia, a Novel SUMO-Targeted Ubiquitin Ligase Involved in PML Degradation

Erker

Neyret‐Kahn

Seeler

et al. 2013

Molecular and Cellular Biology

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bArkadia is a RING domain E3 ubiquitin ligase that activates the transforming growth factor ␤ (TGF-␤) pathway by inducing degradation of the inhibitor SnoN/Ski. Here we show that Arkadia contains three successive SUMO-interacting motifs (SIMs) that mediate noncovalent interaction with poly-SUMO2. We identify the third SIM (VVDL) of Arkadia to be the most relevant one in this interaction. Furthermore, we provide evidence that Arkadia can function as a SUMO-targeted ubiquitin ligase (STUBL) by ubiquitinating SUMO chains. While the SIMs of Arkadia are not essential for SnoN/Ski degradation in response to TGF-␤, we show that they are necessary for the interaction of Arkadia with polysumoylated PML in response to arsenic and its concomitant accumulation into PML nuclear bodies. Moreover, Arkadia depletion leads to accumulation of polysumoylated PML in response to arsenic, highlighting a requirement of Arkadia for arsenic-induced degradation of polysumoylated PML. Interestingly, Arkadia homodimerizes but does not heterodimerize with RNF4, the other STUBL involved in PML degradation, suggesting that these two E3 ligases do not act synergistically but most probably act independently during this process. Altogether, these results identify Arkadia to be a novel STUBL that can trigger degradation of signal-induced polysumoylated proteins.

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Section: Discussionmentioning

confidence: 99%

Arkadia, a Novel SUMO-Targeted Ubiquitin Ligase Involved in PML Degradation

Erker

Neyret‐Kahn

Seeler

et al. 2013

Molecular and Cellular Biology

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“…In addition to telomeres, persistent DNA damage, abruptly shortened telomeres, and a subset of highly transcribed genes are also found to shift to the nuclear periphery (reviewed in Oza and Peterson 2010;Nagai et al 2011). In these cases, the NPC is clearly involved in the peripheral association, and for DSBs and short telomeres an additional pathway implicating Mps3 was described (Nagai et al 2008;Kalocsay et al 2009; Figure 4 Telomere-tethering mechanisms.…”

Section: Minimal Anchoring Assay and The Validation Of Genetic Screensmentioning

confidence: 99%

“…Thus, one scenario is that sumoylated proteins accumulate at collapsed forks or resected breaks that require Slx5/Slx8 ubiquitylation for proteasomal degradation, or alternatively, desumoylation by Ulp1, to enable appropriate repair. Exactly what the relevant protein may be is at present unknown, although Rad51, Rad52, Pol32, PCNA, and other proteins of the replication machinery are heavily sumoylated upon DNA damage (Melchior 2000;Nagai et al 2011;Cremona et al 2012).…”

Section: Mobility Of Dsbsmentioning

confidence: 99%

Structure and Function in the Budding Yeast Nucleus

2012

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Budding yeast, like other eukaryotes, carries its genetic information on chromosomes that are sequestered from other cellular constituents by a double membrane, which forms the nucleus. An elaborate molecular machinery forms large pores that span the double membrane and regulate the traffic of macromolecules into and out of the nucleus. In multicellular eukaryotes, an intermediate filament meshwork formed of lamin proteins bridges from pore to pore and helps the nucleus reform after mitosis. Yeast, however, lacks lamins, and the nuclear envelope is not disrupted during yeast mitosis. The mitotic spindle nucleates from the nucleoplasmic face of the spindle pole body, which is embedded in the nuclear envelope. Surprisingly, the kinetochores remain attached to short microtubules throughout interphase, influencing the position of centromeres in the interphase nucleus, and telomeres are found clustered in foci at the nuclear periphery. In addition to this chromosomal organization, the yeast nucleus is functionally compartmentalized to allow efficient gene expression, repression, RNA processing, genomic replication, and repair. The formation of functional subcompartments is achieved in the nucleus without intranuclear membranes and depends instead on sequence elements, protein-protein interactions, specific anchorage sites at the nuclear envelope or at pores, and long-range contacts between specific chromosomal loci, such as telomeres. Here we review the spatial organization of the budding yeast nucleus, the proteins involved in forming nuclear subcompartments, and evidence suggesting that the spatial organization of the nucleus is important for nuclear function. TABLE OF CONTENTS Abstract 107Introduction 108

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“…In mammalian cells, UBC9 is the only SUMOylation E2 enzyme, and the E3 ligases are considered to be important for proper activity and target selection (Cubeñas-Potts and Matunis, 2013). Several lines of evidence suggest the involvement of the SUMO modification system in DNA repair (Kalocsay et al, 2009;Galanty et al, 2009;Morris et al, 2009;Nagai et al, 2011;Ulrich, 2012;Jackson and Durocher, 2013). SUMOylation of PCNA inhibits PCNA-dependent DNA repair of lesions induced by UV exposure or methylmethane sulfonate treatment in budding yeast (Hoege et al, 2002).…”

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confidence: 99%

Activation of the SUMO modification system is required for the accumulation of RAD51 at sites containing DNA damage

Shima

Suzuki

Sun

et al. 2013

Journal of Cell Science

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SummaryGenetic information encoded in chromosomal DNA is challenged by intrinsic and exogenous sources of DNA damage. DNA doublestrand breaks (DSBs) are extremely dangerous DNA lesions. RAD51 plays a central role in homologous DSB repair, by facilitating the recombination of damaged DNA with intact DNA in eukaryotes. RAD51 accumulates at sites containing DNA damage to form nuclear foci. However, the mechanism of RAD51 accumulation at sites of DNA damage is still unclear. Post-translational modifications of proteins, such as phosphorylation, acetylation and ubiquitylation play a role in the regulation of protein localization and dynamics. Recently, the covalent binding of small ubiquitin-like modifier (SUMO) proteins to target proteins, termed SUMOylation, at sites containing DNA damage has been shown to play a role in the regulation of the DNA-damage response. Here, we show that the SUMOylation E2 ligase UBC9, and E3 ligases PIAS1 and PIAS4, are required for RAD51 accretion at sites containing DNA damage in human cells. Moreover, we identified a SUMO-interacting motif (SIM) in RAD51, which is necessary for accumulation of RAD51 at sites of DNA damage. These findings suggest that the SUMO-SIM system plays an important role in DNA repair, through the regulation of RAD51 dynamics.

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Nuclear organization in genome stability: SUMO connections

Cited by 83 publications

References 100 publications

Arkadia, a Novel SUMO-Targeted Ubiquitin Ligase Involved in PML Degradation

Arkadia, a Novel SUMO-Targeted Ubiquitin Ligase Involved in PML Degradation

Structure and Function in the Budding Yeast Nucleus

Activation of the SUMO modification system is required for the accumulation of RAD51 at sites containing DNA damage

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