Functional Targeting of DNA Damage to a Nuclear Pore-Associated SUMO-Dependent Ubiquitin Ligase

Nagai, Shoichi; Dubrana, Karine; Tsai-Pflugfelder, Monika; Davidson, Marta B.; Roberts, Tania Michelle; Brown, Grant W.; Varela, Elisa; Hediger, Florence; Gasser, Susan M.; Krogan, Nevan J.

doi:10.1126/science.1162790

Cited by 412 publications

(591 citation statements)

References 32 publications

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“…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 certain components of the yeast nuclear pore complex, like NUP84 and the nucleoporin NUP60, located in the basket of the pore. 5,6 Additional studies revealed that depletion of representative members of the NUP84 or NUP60 complex leads to synthetic lethality when combined with genes that are required for DSBR through HR.…”

Section: Introductionmentioning

confidence: 99%

“…5,6 This sequestration to the nuclear periphery was shown to require certain components of the yeast nuclear pore complex, like NUP84 and the nucleoporin NUP60, located in the basket of the pore. 5,6 Additional studies revealed that depletion of representative members of the NUP84 or NUP60 complex leads to synthetic lethality when combined with genes that are required for DSBR through HR. 4 Moreover, mutants of the NUP84 complex are highly sensitive to DNA-damaging treatments.…”

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…In yeast, these locations are the nuclear pore subcomplex Nup84 (composed of seven entities, including Nup84 and Nup145) as well as the Mps3 inner nuclear membrane protein [12][13][14][15] . In fact, DSBs in cells without clear donor DNA sites for repair relocate at least transiently to Nup84 or Mps3 proteins [12][13][14][15] .…”

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confidence: 99%

Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process

et al. 2015

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DNA double-strand breaks (DSBs) are often targeted to nuclear pore complexes (NPCs) for repair. How targeting is achieved and the DNA repair pathways involved in this process remain unclear. Here, we show that the kinesin-14 motor protein complex (Cik1-Kar3) cooperates with chromatin remodellers to mediate interactions between subtelomeric DSBs and the Nup84 nuclear pore complex to ensure cell survival via break-induced replication (BIR), an error-prone DNA repair process. Insertion of a DNA zip code near the subtelomeric DSB site artificially targets it to NPCs hyperactivating this repair mechanism. Kinesin-14 and Nup84 mediate BIR-dependent repair at non-telomeric DSBs whereas perinuclear telomere tethers are only required for telomeric BIR. Furthermore, kinesin-14 plays a critical role in telomerase-independent telomere maintenance. Thus, we uncover roles for kinesin and NPCs in DNA repair by BIR and reveal that perinuclear telomere anchors license subtelomeric DSBs for this error-prone DNA repair mechanism.

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“…Des études pionnières ont ainsi montré que les chromosomes de la levure ont un mouvement confiné ne leur permettant d'explorer qu'un petit volume du noyau [4,5]. De récentes études suggèrent indirectement un changement de mobilité de l'ADN qui a subi une lésion [6][7][8][9][10][11][12], mais le mécanisme permettant à cet ADN endommagé de trouver son 1 Dans le cas d'un mouvement brownien à une dimension (ligne droite), le déplacement d'une particule peut se faire soit en « pas » en avant, soit en « pas » en arrière. De plus, il est impossible de prédire cette direction, l'une (avant) et l'autre (arrière) étant équiprobables.…”

Section: Les Chromosomes Explorent Leur Environnementunclassified

Réparation de l’ADN

Miné-Hattab

Rothstein

2012

Med Sci (Paris)

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Functional Targeting of DNA Damage to a Nuclear Pore-Associated SUMO-Dependent Ubiquitin Ligase

Cited by 412 publications

References 32 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

Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process

Réparation de l’ADN

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