The Ku heterodimer: Function in DNA repair and beyond

Fell, Victoria L.; Schild-Poulter, Caroline

doi:10.1016/j.mrrev.2014.06.002

Cited by 229 publications

(226 citation statements)

References 251 publications

(285 reference statements)

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“…The key regulators of this pathway are a pair of Ku proteins, Ku70 and Ku80, which form a heterodimer and are the first proteins to bind broken DNA ends (171). There they act as a scaffold to recruit and assemble the DNA repair machinery.…”

mentioning

confidence: 99%

F-box protein interactions with the hallmark pathways in cancer

Randle

Laman

2016

Seminars in Cancer Biology

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F-box proteins (FBP) are the substrate specifying subunit of Skp1-Cul1-FBP (SCF)-type E3 ubiquitin ligases and are responsible for directing the ubiquitination of numerous proteins essential for cellular function. Due to their ability to regulate the expression and activity of oncogenes and tumour suppressor genes, FBPs themselves play important roles in cancer development and progression. In this review, we provide a comprehensive overview of FBPs and their targets in relation to their interaction with the hallmarks of cancer cell biology, including the regulation of proliferation, epigenetics, migration and invasion, metabolism, angiogenesis, cell death and DNA damage responses. Each cancer hallmark is revealed to have multiple FBPs which converge on common signalling hubs or response pathways. We also highlight the complex regulatory interplay between SCF-type ligases and other ubiquitin ligases. We suggest six highly interconnected FBPs affecting multiple cancer hallmarks, which may prove sensible candidates for therapeutic intervention.

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confidence: 99%

F-box protein interactions with the hallmark pathways in cancer

Randle

Laman

2016

Seminars in Cancer Biology

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“…As such, it has acquired a number of functions throughout evolution, ranging from DNA repair and transcription to regulation of virus pathogenicity (Masson et al, 2007;Fell and Schild-Poulter, 2015). The most perplexing is its counterintuitive involvement in telomere biology that seemingly contradicts its canonical role in C-NHEJ.…”

Section: Discussionmentioning

confidence: 99%

“…Ku is a DNA binding complex with a high affinity for DNA ends. It consists of Ku70 and Ku80 subunits that form a ring-like structure with a preformed channel that slides onto free DNA ends (Walker et al, 2001;Fell and Schild-Poulter, 2015). Ku has multiple functions in C-NHEJ.…”

Section: Introductionmentioning

confidence: 99%

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Protection of Arabidopsis Blunt-Ended Telomeres Is Mediated by a Physical Association with the Ku Heterodimer

et al. 2017

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Telomeres form specialized chromatin that protects natural chromosome termini from being recognized as DNA doublestrand breaks. Plants possess unusual blunt-ended telomeres that are unable to form t-loops or complex with single-strand DNA binding proteins, raising the question of the mechanism behind their protection. We have previously suggested that blunt-ended telomeres in Arabidopsis thaliana are protected by Ku, a DNA repair factor with a high affinity for DNA ends. In nonhomologous end joining, Ku loads onto broken DNA via a channel consisting of positively charged amino acids. Here, we demonstrate that while association of Ku with plant telomeres also depends on this channel, Ku's requirements for DNA binding differ between DNA repair and telomere protection. We show that a Ku complex proficient in DNA loading but impaired in translocation along DNA is able to protect blunt-ended telomeres but is deficient in DNA repair. This suggests that Ku physically sequesters blunt-ended telomeres within its DNA binding channel, shielding them from other DNA repair machineries.

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“…It is possible that the DNA ends of a large subset of DSBs are maintained at proximity by the static nature of heterochromatin structures prior to initiation of the DNA damage signaling. The abundance of Ku70/Ku80 may allow the rapid binding of Ku7/ Ku80 to the DNA ends in heterochromatin even before the relaxation of heterochromatin [50,127]. This binding not only prevents end resection, but also activates the NHEJ repair pathway.…”

Section: Discussionmentioning

confidence: 99%

Buried territories: heterochromatic response to DNA double-strand breaks

Feng¹,

Xiang²,

Kong³

et al. 2016

ABBS

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Cellular response to DNA double-strand breaks (DSBs), the most deleterious type of DNA damage, is highly influenced by higher-order chromatin structure in eukaryotic cells. Compared with euchromatin, the compacted structure of heterochromatin not only protects heterochromatic DNA from damage, but also adds an extra layer of control over the response to DSBs occurring in heterochromatin. One key step in this response is the decondensation of heterochromatin structure. This decondensation process facilitates the DNA damage signaling and promotes proper heterochromatic DSB repair, thus helping to prevent instability of heterochromatic regions of genomes. This review will focus on the functions of the ataxia telangiectasia mutated (ATM) signaling cascade involving ATM, heterochromatin protein 1 (HP1), Krüppel-associated box (KRAB)-associated protein-1 (KAP-1), tat-interacting protein 60 (Tip60), and many other protein factors in DSB-induced decondensation of heterochromatin and subsequent repair of heterochromatic DSBs. As some subsets of DSBs may be repaired in heterochromatin independently of the ATM signaling, a possible repair model is also proposed for ATM-independent repair of these heterochromatic DSBs.

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The Ku heterodimer: Function in DNA repair and beyond

Cited by 229 publications

References 251 publications

F-box protein interactions with the hallmark pathways in cancer

F-box protein interactions with the hallmark pathways in cancer

Protection of Arabidopsis Blunt-Ended Telomeres Is Mediated by a Physical Association with the Ku Heterodimer

Buried territories: heterochromatic response to DNA double-strand breaks

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