Ku's essential role in keeping telomeres intact

Indiviglio, Sandra M.; Bertuch, Alison A.

doi:10.1073/pnas.0906427106

Cited by 19 publications

(27 citation statements)

References 19 publications

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“…In a previous study using the Ku86 flox/− cell line, we observed that the removal of all Ku86 expression from the HCT116 cell line resulted in rapid telomere loss and the apparent high frequency fusion of sister chromatids (24,25). Where it has been examined, telomere fusions in mammalian cells generally [see, however, (61,62) for reports to the contrary] are mediated by LIGIV.…”

Section: Resultsmentioning

confidence: 91%

“…For example, the Ku heterodimer, and possibly DNA-PK cs , is part of the t-loop-associated complex (21–23). Interestingly, telomere protection by the Ku complex is essential in human cells because Ku loss-of-function mutations provoke cell death triggered by telomere dysfunction (24,25). All of the C-NHEJ factors, however, are unlikely to be involved in telomere maintenance, and there is, for example, little evidence for a role for DNA Ligase IV (LIGIV), or its accessory factors, X-ray cross-complementing group 4 (XRCC4) and XRCC4-like factor (XLF) in normal telomere maintenance.…”

Section: Introductionmentioning

confidence: 99%

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Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction

Wang

Zimbric

et al. 2012

Nucleic Acids Research

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Classic non-homologous end joining (C-NHEJ) is the predominant DNA double-strand break repair pathway in humans. Although seven genes Ku70, Ku86, DNA-PKcs, Artemis, DNA Ligase IV (LIGIV), X-ray cross-complementing group 4 and XRCC4-like factor are required for C-NHEJ, several of them also have ancillary functions. For example, Ku70:Ku86 possesses an essential telomere maintenance activity. In contrast, LIGIV is believed to function exclusively in C-NHEJ. Moreover, a viable LIGIV-null human B-cell line and LIGIV-reduced patient cell lines have been described. Together, these observations suggest that LIGIV (and hence C-NHEJ), albeit important, is nonetheless dispensable, whereas Ku70:Ku86 and telomere maintenance are essential. To confirm this hypothesis, we inactivated LIGIV in the epithelial human cell line, HCT116. The resulting LIGIV-null cell line was viable, verifying that the gene and C-NHEJ are not essential. However, functional inactivation of RAD54B, a key homologous recombination factor, in the LIGIV-null background yielded no viable clones, suggesting that the combined absence of RAD54B/homologous recombination and C-NHEJ is synthetically lethal. Finally, we demonstrate that LIGIV is differentially required for certain chromosome fusion events induced by telomere dysfunction—used for those owing to the overexpression of a dominant negative version of telomere recognition factor 2, but not used for those owing to absence of Ku70:Ku86.

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Section: Resultsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction

Wang

Zimbric

et al. 2012

Nucleic Acids Research

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“…, 2009; Xiao et al. , 2015), and telomere maintenance (Indiviglio and Bertuch, 2009). XRCC5/6 localizes to DSB sites after DNA damage (Britton et al.…”

Section: Discussionmentioning

confidence: 99%

Chromatin association of XRCC5/6 in the absence of DNA damage depends on the XPE gene product DDB2

Fantini

Huang

Asara

et al. 2017

MBoC

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Damaged DNA-binding protein 2 (DDB2), a nuclear protein, participates in both nucleotide excision repair and mRNA transcription. The transcriptional regulatory function of DDB2 is significant in colon cancer, as it regulates metastasis. To characterize the mechanism by which DDB2 participates in transcription, we investigated the protein partners in colon cancer cells. Here we show that DDB2 abundantly associates with XRCC5/6, not involving CUL4 and DNA-PKcs. A DNA-damaging agent that induces DNA double-stranded breaks (DSBs) does not affect the interaction between DDB2 and XRCC5. In addition, DSB-induced nuclear enrichment or chromatin association of XRCC5 does not involve DDB2, suggesting that the DDB2/XRCC5/6 complex represents a distinct pool of XRCC5/6 that is not directly involved in DNA break repair (NHEJ). In the absence of DNA damage, on the other hand, chromatin association of XRCC5 requires DDB2. We show that DDB2 recruits XRCC5 onto the promoter of SEMA3A, a DDB2-stimulated gene. Moreover, depletion of XRCC5 inhibits SEMA3A expression without affecting expression of VEGFA, a repression target of DDB2. Together our results show that DDB2 is critical for chromatin association of XRCC5/6 in the absence of DNA damage and provide evidence that XRCC5/6 are functional partners of DDB2 in its transcriptional stimulatory activity. INTRODUCTIONDDB2, a product of the xeroderma pigmentosum group E (XPE) gene, plays important roles in the early steps of global genomic repair through the nucleotide excision repair (NER) pathway (Tang and Chu, 2002). It associates with the CUL4-DDB1 E3 ligase (Shiyanov et al., 1999b) to ubiquitinate histones and the NER protein XPC, leading to assembly of the NER repair complex on the damaged chromatin (Wang et al., 2004(Wang et al., , 2006Kapetanaki et al., 2006). In addition, DDB2 has a chromatin-remodeling activity that supports NER . It has been suggested DDB2 cooperates with PARP1 to stimulate NER . DDB2 also possesses transcriptional regulatory activities. Mouse embryonic fibroblasts (MEFs) lacking DDB2 are deficient in undergoing senescence in culture, which is linked to an increase in antioxidant activities. DDB2 represses expression of the antioxidant genes MnSOD and Catalase (Minig et al., 2009;Roy et al., 2010). In DDB2 −/− cells or tissues, there is derepression of MnSOD and Catalase, which inhibits accumulation of reactive oxygen species (ROS). In colon cancer cells, depletion of DDB2 leads to epithelial-to-mesenchymal transition (EMT), which is associated with aggressive tumor progression and increased liver metastasis (Roy et al., 2013). The EMT and increased metastasis was related to derepression of Zeb1, Snail, and VEGFA expression. In mesenchymal-type colon cancer cells having reduced expression of DDB2, reexpression of DDB2 causes Monitoring Editor

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“…The frequency of telomere fusion is higher in ALT cells than in control cells, and it has been suggested that Ku70/80 plays a major role in telomere fusion in ALT cells (Espejel et al , 2002). However, telomere fusion also occurs in Ku70 − / − /80 − / − MEFs depleted in shelterin proteins TRF1/2 (Rai et al , 2010), suggesting that telomere fusion is supported by an alternative end joining pathway (Indiviglio & Bertuch, 2009; Sfeir & de Lange, 2012). PARP1 promotes B-NHEJ.…”

Section: Telomere Maintenancementioning

confidence: 99%

The role of RecQ helicases in non-homologous end-joining

Keijzers

Maynard

Shamanna

et al. 2014

Critical Reviews in Biochemistry and Molecular Biology

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DNA double-strand breaks are highly toxic DNA lesions that cause genomic instability, if not efficiently repaired. RecQ helicases are a family of highly conserved proteins that maintain genomic stability through their important roles in several DNA repair pathways, including DNA double-strand break repair. Double-strand breaks can be repaired by homologous recombination (HR) using sister chromatids as templates to facilitate precise DNA repair, or by an HR-independent mechanism known as non-homologous end-joining (NHEJ) (error-prone). NHEJ is a non-templated DNA repair process, in which DNA termini are directly ligated. Canonical NHEJ requires DNA-PKcs and Ku70/80, while alternative NHEJ pathways are DNA-PKcs and Ku70/80 independent. This review discusses the role of RecQ helicases in NHEJ, alternative (or back-up) NHEJ (B-NHEJ) and microhomology-mediated end-joining (MMEJ) in V(D)J recombination, class switch recombination and telomere maintenance.

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Ku's essential role in keeping telomeres intact

Cited by 19 publications

References 19 publications

Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction

Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction

Chromatin association of XRCC5/6 in the absence of DNA damage depends on the XPE gene product DDB2

The role of RecQ helicases in non-homologous end-joining

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