Nucleoporins Prevent DNA Damage Accumulation by Modulating Ulp1-dependent Sumoylation Processes

Palancade, Benoı̂t; Liu, Xianpeng; García-Rubio, María L.; Aguilera, Andrés; Zhao, Xiaolan; Doye, Valérie

doi:10.1091/mbc.e07-02-0123

Cited by 131 publications

(175 citation statements)

References 51 publications

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“…In yeast, the nucleoporin complexes NUP84 (hNUP107) and NUP60 (hNUP153) protect against genomic instability through maintenance of proper levels of the sumo protease Ulp1 at NPCs, and through appropriate sumoylation of several proteins, including yKu. 25 It is tempting to speculate that a similar mechanism is conserved in mammals. Furthermore, it would be very interesting to investigate whether the role of NUP153 in DDR is unique or if other mammalian nucleoporins have similar role.…”

Section: Resultsmentioning

confidence: 99%

The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response

et al. 2012

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DNA repair is essential in maintaining genome integrity and defects in different steps of the process have been linked to cancer and aging. It is a long lasting question how DNA repair is spatially and temporarily organized in the highly compartmentalized nucleus and whether the diverse nuclear compartments regulate differently the efficiency of repair. Increasing evidence suggest the involvement of nuclear pore complexes in repair of double-strand breaks (DSBs) in yeast. Here, we show that the human nucleoporin 153 (NUP153) has a role in repair of DSBs and in the activation of DNA damage checkpoints. We explore the mechanism of action of NUP153 and we propose its potential as a novel therapeutic target in cancers.Oncogene ( Keywords: DNA repair; nuclear pore; 53BP1 INTRODUCTION DNA double-strand breaks (DSBs) are particularly dangerous as their inefficient or inaccurate repair can result in mutations and chromosomal translocations that may induce cancer. 1 DSBs can be repaired by one of two major pathways: homology-based repair (homologous recombination (HR)) using the intact chromatid as a template present in proximity in S and G2 phases of the cell cycle, or direct joining across the break site (non-homologous end joining (NHEJ)). 2 The coordination between cell cycle progression and DSB repair (DSBR) is regulated by the DNA damage response (DDR) signalling pathway, which activates the cell cycle checkpoints in the presence of DNA breaks. 3 This pathway is initiated by the recruitment of the MRN (MRE11 --RAD50 --NBS1) sensor complex to sites of damage. The recruitment of MRN subsequently activates the ATM kinase, which associates with DSBs and phosphorylates the histone variant H2AX (g-H2AX). 2 MDC1 can then bind to gH2AX and recruit new MRN and ATM proteins, leading to spreading of the repair machinery along the chromosome. MDC1 also recruits ubiquitin ligases, such as RNF8 and RNF168, which facilitate the recruitment of the downstream factors 53BP1 and BRCA1. 2 When the DNA is resected to singlestranded DNA, it is recognized by replication protein A, which results in the recruitment of ATR. 2 Both the ATM and the ATR dependent branches of the pathway lead to the activation of the checkpoint kinases, CHK1 and CHK2, which stall damaged cells in their cell cycle until the lesions are resolved. 3 DNA repair, like all DNA-dependent processes, occur in the highly compartmentalized nucleus. Most nuclear events do not occur ubiquitously, but are limited to defined sites. 2 Several studies in yeast have shown that dedicated DNA repair centres exist as preferential sites of repair. 2,4 Furthermore, persistent DSBs in yeast migrate from their internal nuclear positions to the nuclear periphery, where they associate with nuclear pores. 5,6 This sequestration to the nuclear periphery was shown to require

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Section: Resultsmentioning

confidence: 99%

The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response

et al. 2012

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“…Notably, in addition to causing impaired nuclear transport, the temperature-sensitive mutant of Ulp1 accumulates single-stranded DNA during genome replication and has a hyper-recombination phenotype [56]. Furthermore, both the conditional ulp1 mutant and deletions of mlp1 or mlp2 are synthetically lethal with the loss or mutation of genes involved in HR [52,56,57]. The genomic instability observed in mutants of Mlp1/Mlp2 or Nup84 complex components correlates with a drop in Ulp1 protein levels; consistently, overexpression of Ulp1 partially suppresses the genomic instability observed in these mutants [57,58].…”

Section: Nuclear Envelope and Genome Stability: Sumo Connectionsmentioning

confidence: 99%

“…Furthermore, both the conditional ulp1 mutant and deletions of mlp1 or mlp2 are synthetically lethal with the loss or mutation of genes involved in HR [52,56,57]. The genomic instability observed in mutants of Mlp1/Mlp2 or Nup84 complex components correlates with a drop in Ulp1 protein levels; consistently, overexpression of Ulp1 partially suppresses the genomic instability observed in these mutants [57,58]. These studies suggested that nuclear pores may play an important role in the maintenance of genome stability by facilitating or coordinating SUMO metabolism.…”

Section: Nuclear Envelope and Genome Stability: Sumo Connectionsmentioning

confidence: 99%

Nuclear organization in genome stability: SUMO connections

2011

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Recent findings show that chromatin dynamics and nuclear organization are not only important for gene regulation and DNA replication, but also for the maintenance of genome stability. In yeast, nuclear pores play a role in the maintenance of genome stability by means of the evolutionarily conserved family of SUMO-targeted Ubiquitin ligases (STUbLs). The yeast Slx5/Slx8 STUbL associates with a class of DNA breaks that are shifted to nuclear pores. Functionally Slx5/Slx8 are needed for telomere maintenance by an unusual recombination-mediated pathway. The mammalian STUbL RNF4 associates with Promyelocytic leukaemia (PML) nuclear bodies and regulates PML/PMLfusion protein stability in response to arsenic-induced stress. A subclass of PML bodies support telomere maintenance by the ALT pathway in telomerase-deficient tumors. Perturbation of nuclear organization through either loss of pore subunits in yeast, or PML body perturbation in man, can lead to gene amplifications, deletions, translocations or endto-end telomere fusion events, thus implicating SUMO and STUbLs in the subnuclear organization of select repair events.

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“…For instance, the essential yeast SUMO peptidase, Ulp1, is associated with the NPC, and loss of its peripheral localization leads to DNA damage phenotypes reminiscent of nup84 mutants. [47][48][49] Likewise, the Slx5 and Slx8 SUMOtargeted ubiquitin ligases map to the same E-MAP group as Nup84 and RAD52 group members, and Slx5 and Slx8 associate with NPCs and can be detected by ChIP at a persistent DSB. 20 SLX5 and SLX8 were first identified in a screen for mutants that show synthetic lethality with mutations in the SGS1 gene that encodes a homolog of the RecQ helicase.…”

Section: Introductionmentioning

confidence: 99%

Opening the DNA repair toolbox: Localization of DNA double strand breaks to the nuclear periphery

Oza¹,

Peterson²

2010

Cell Cycle

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E fficient repair of DNA double strand breaks is essential for cells to avoid increased mutation rates, genomic instability, and even cell death. Consequently, cells have evolved multiple mechanisms for rapidly repairing these DNA lesions, including error-free homologous recombination as well as error-prone pathways such as nonhomologous end joining. What happens to DSBs that are repaired inefficiently or not at all? Recently, several studies in budding yeast have shown that these more recalcitrant DSBs are localized to the nuclear periphery through interactions between the nuclear envelope protein, Mps3, and proteins associated with DSB chromatin. Why these DSBs are tethered to the nuclear periphery is still not clear, though the current view is that alternative repair pathways may be activated at the periphery in a final attempt to repair the lesion. In this Extra View, we discuss these recent reports, and we show that the Est1 component of the telomerase machinery plays an essential role in anchoring DSB chromatin to the nuclear envelope protein, Mps3.

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Nucleoporins Prevent DNA Damage Accumulation by Modulating Ulp1-dependent Sumoylation Processes

Cited by 131 publications

References 51 publications

The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response

The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response

Nuclear organization in genome stability: SUMO connections

Opening the DNA repair toolbox: Localization of DNA double strand breaks to the nuclear periphery

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