Impact of the KU80 Pathway on NHEJ-Induced Genome Rearrangements in Mammalian Cells

Guirouilh‐Barbat, Josée; Huck, Sylvie; Bertrand, Pascale; Pirzio, Livia Maria; Desmaze, Chantal; Sabatier, Laure; Lopez, Bernard S.

doi:10.1016/j.molcel.2004.05.008

Cited by 288 publications

(361 citation statements)

References 30 publications

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“…Among the different rearrangements, deletions are two-to eightfold more frequent than inversion. This may be due in part to the fact that deletion and inversion require one and two ligation events, respectively (Guirouilh-Barbat et al, 2004). Our results demonstrated that only full-length Vpr affects Ku endogenous levels and disturbs Ku's protective role by preventing NHEJ.…”

Section: Discussionmentioning

confidence: 70%

Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin

et al. 2007

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Section: Discussionmentioning

confidence: 70%

Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin

et al. 2007

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“…To this end, we utilized cell lines that contain stably integrated reporters to assess the rates of HR (DR-GFP 10,11 ) and NHEJ. 12 --14 For NHEJ, we used cell lines containing two types of NHEJ-reporter substrates; the pCOH-CD4 that permits analysis of the NHEJ of two distal ends (separated by 3.2 kb), 12,13 and a GFP-based substrate, 14 to measure the NHEJ on closely adjacent ends, separated by only 34 bp. 14 Figure 1.…”

Section: Resultsmentioning

confidence: 99%

“…However, silencing of classical NHEJ factors that affect the efficiency of end ligation affect the fidelity of repair as well. 13 An alternative scenario could be that NUP153 negatively regulates a protein that promotes HR. Furthermore, we can imagine that the nuclear soluble fraction of 53BP1 has a role in the regulation of the repair pathways, by sequestering certain factors away from the break.…”

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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“…Defects in HR or in NHEJ can lead to genome instability and tumorigenesis (Liu et al, 1998;Sonoda et al, 1998;Difilippantonio et al, 2000;Ferguson et al, 2000a;Bertrand et al, 2003). However, both functional HR and NHEJ can be responsible for genome rearrangements: (i) functional HR between repeated sequences dispersed through the genome can also lead to genome rearrangements (Purandare and Patel, 1997;Richardson and Jasin, 2000b;Bertrand et al, 2004), and (ii) functional Ku autoantigen protein (KU)-dependent as well as KU-independent NHEJ can generate genetic rearrangements (Guirouilh-Barbat et al, 2004). This shows the importance of a precise DSB repair regulation in mammalian cells for the equilibrium between genetic stability and diversity.…”

Section: Introductionmentioning

confidence: 99%

XRCC4 in G1 suppresses homologous recombination in S/G2, in G1 checkpoint-defective cells

et al. 2006

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Non-homologous end joining (NHEJ) and homologous recombination (HR) are two pathways that can compete or cooperate for DNA double-strand break (DSB) repair. NHEJ was previously shown to act throughout the cell cycle whereas HR is restricted to late S/G2. Paradoxically, we show here that defect in XRCC4 (NHEJ) leads to over-stimulation of HR when cells were irradiated in G1, not in G2. However, XRCC4 defect did not modify the strict cell cycle regulation for HR (i.e. in S/G2) as attested by (i) the formation of Rad51 foci in late S/G2 whatever the XRCC4 status, and (ii) the fact that neither Rad51 foci nor HR (gene conversion plus single-strand annealing) events induced by ionizing radiation were detected when cells were maintained blocked in G1. Finally, both c-H2AX analysis and pulse field gel electrophoresis showed that following irradiation in G1, some DSBs reached S/G2 in NHEJ-defective cells. Taken together, our results show that when cells are defective in G1/S arrest, DSB produced in G1 and left unrepaired by XRCC4 can be processed by HR but in late S/G2.

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Impact of the KU80 Pathway on NHEJ-Induced Genome Rearrangements in Mammalian Cells

Cited by 288 publications

References 30 publications

Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin

Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin

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

XRCC4 in G1 suppresses homologous recombination in S/G2, in G1 checkpoint-defective cells

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