Binding to the Minor Groove of the Double-Strand, Tau Protein Prevents DNA from Damage by Peroxidation

Wei, Yan; Qu, Mei-Hua; Wang, Xing-Sheng; Chen, Lan; Wang, Dongliang; Liu, Ying; Hua, Qian; He, Rong

doi:10.1371/journal.pone.0002600

Cited by 106 publications

(110 citation statements)

References 46 publications

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“…The new interest extends to the nucleus where tau is believed to have an important scaffolding function [13,27]. Because, in the past, data on nuclear tau expression have been inconsistent, in part because of different fixation methods and experimental systems, we validated three principal methods: immunocytochemical staining of human and murine neuroblastoma cell lines testing six protocols, subcellular fractionation of wild-type and human tau transgenic mouse brain, and isolation of nuclei from mouse brain.…”

Section: Discussionmentioning

confidence: 99%

“…The punctate pattern seen for Tau-1 in our immunocytochemical study in SH-SY5Y cells is reminiscent of that of nucleoli although this has not been further investigated. In vitro studies further revealed that purified tau binds to AT-rich sequences in the minor groove of DNA [27]. Using an electrophoretic mobility shift assay (EMSA) it was shown that both the proline-rich domain and the microtubule-binding domain contribute to the interaction of tau with DNA.…”

Section: Discussionmentioning

confidence: 99%

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Visualizing the microtubule-associated protein tau in the nucleus

Lü

et al. 2014

Sci. China Life Sci.

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Although tau is mainly known as an axonal microtubule-associated protein, many studies indicate that it is not restricted to this subcellular compartment. Assessing tau's subcellular distribution, however, is not trivial as is evident from transgenic mouse studies. When human tau is over-expressed, it can be immunohistochemically localized to axons and the somatodendritic domain, modeling what is found in neurodegenerative diseases such as Alzheimer's disease. Yet, in wild-type mice, despite its abundance, tau is difficult to visualize even in the axon. It is even more challenging to detect this protein in the nucleus, where tau has been proposed to protect DNA from damage. To establish a framework for future studies into tau's nuclear functions, we compared several methods to visualize endogenous nuclear tau in cell lines and mouse brain. While depending on the fixation and permeabilization protocol, we were able to detect nuclear tau in SH-SY5Y human neuroblastoma cells, we failed to do so in N2a murine neuroblastoma cells. As a second method we used subcellular fractionation of mouse tissue and found that in the nucleus tau is mainly present in a hypophosphorylated form. When either full-length or truncated human tau was expressed, both accumulated in the cytoplasm, but were also found in the nuclear fraction. Because subcellular fractionation methods have their limitations, we finally isolated nuclei to probe for nuclear tau and found that the nuclei were free of cytoplasmic contamination. Together our analysis identifies several protocols for detecting tau in the nucleus where it is found in a less phosphorylated form.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Visualizing the microtubule-associated protein tau in the nucleus

Lü

et al. 2014

Sci. China Life Sci.

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“…Other studies have reported that nuclear Tau binds preferentially to polynucleotides of 13 bp in length, while further research has indicated that Tau binds to the minor groove of the DNA double helix and that both its proline-rich domain (PRD) and microtubulebinding domain (MTBD) contribute to its interaction with DNA. This binding protects DNA from both digestion by DNase I and damage by peroxidation (Wei et al, 2008).…”

Section: Formaldehyde-induced Aggregation Interferes With Tau's Protementioning

confidence: 99%

Chronic Formaldehyde-Mediated Impairments and Age-Related Dementia

Miao¹,

He²

2012

Neurodegeneration

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“…Tau has been reported to bind single-and double-stranded DNA via the minor groove (26,27,84,85), thereby drawing parallels between Tau and histones in terms of DNA binding. Indeed, monomers or small oligomers of Tau can bind to DNA complexes and give rise to a "beads-on-a-string" organization like histone-DNA assembly (80,84), thus suggesting that Tau could act like a chaperone (26,27,84). Although larger aggregates of Tau interact only weakly with DNA (84,86), complexes between large Tau aggregates and DNA have been observed in vitro, suggesting that different Tau-DNA structures exist (84).…”

Section: Aicd A␤42 and Tau Interactions With Dnamentioning

confidence: 99%

“…In vitro, Wei et al (80) showed that Tau-DNA binding protected DNA from damage induced by free hydroxyl radicals, likely through its capacity to bind to the AT-rich minor groove of DNA (i.e. a common way for proteins to physically protect DNA from damage by inducing its bending).…”

Section: Possible Nuclear Functions Of Aicd A␤ and Taumentioning

confidence: 99%

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

Multhaup

Huber

Buée

et al. 2015

Journal of Biological Chemistry

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Alzheimer disease (AD) 2 is the most common form of dementia and a leading cause of death. Amyloid-␤ (A␤) peptides of varying length (30 -51 amino acid residues) are produced by the sequential, proteolytic processing of the amyloid precursor protein (APP) by ␤-and ␥-secretases (1, 2). In the healthy brain, these protein fragments are normally degraded and eliminated. In the AD brain, the 42-amino acid peptide (A␤42) is prone to form aggregated amyloid oligomers, which are believed to contribute to plaque formation and cognitive decline (3-6).The ␥-secretase also liberates an intracellular fragment called AICD composed of up to 50 residues depending on N-terminal variations (7-9). The first identification of the APP intracellular fragment (AICD) and its detection in brain tissue (8) immediately suggested that it has transcriptional activity, like the Notch intracellular domain (NICD). Whether amyloid A␤ represents a biologically inert bypass product of APP processing or can harbor its own function is a leading question in the AD field. A␤ is potentially toxic depending on its biophysical state (10). Equimolar amounts of the A␤ peptides and the C-terminal fragment AICD are derived from the ␤-C-terminal fragment C99 (11), which represents the APP fragment generated by the initial APP cleavage by ␤-secretase (Fig. 1).A seminal discovery concerning the transcriptional regulatory function of the APP cytoplasmic tail was the observation of its complex formation with Fe65 and the histone acetyltransferase Tip60 and transcriptional activity in reporter gene assays (12). Transactivation of transcription requires ␥-secretase activity and nuclear translocation of Fe65 but not of AICD under these assay conditions (13). However, other studies detected AICD in transcriptional complexes on promoters of target genes using ChIP (see below).In addition, there is evidence that soluble APP fragments (sAPP) of the ectodomain can modulate gene transcription in stimulating downstream signaling through unknown sAPP receptor(s) (14). Accumulation of intracellular A␤ species in neuronal cells before plaque formation leading to concomitant loss of MAP2 expression suggested that A␤ may affect expression or turnover of other proteins (15-17). However, it was not clarified whether this occurs at the transcriptional or translational level.Using a variety of techniques, the recently detected uptake of A␤ peptides into the nuclei of cultured cells (as well as in vivo) revealed that A␤42 possesses unique modulatory activity (18). Direct evidence for the presence of (i) nuclear A␤42 in wildtype animals, (ii) the increased level of nuclear A␤42 in APPoverexpressing animals, and (iii) the detection of nuclear A␤ in quantities comparable with other transcription factors imply a certain biological relevance.The second major hallmark of AD pathology is the presence of neurofibrillary tangles and is associated with intracellular Tau aggregates called neurofibrillary tangles and with modified Tau (19). Although the neuronal Tau (tubulin-associated unit...

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Binding to the Minor Groove of the Double-Strand, Tau Protein Prevents DNA from Damage by Peroxidation

Cited by 106 publications

References 46 publications

Visualizing the microtubule-associated protein tau in the nucleus

Visualizing the microtubule-associated protein tau in the nucleus

Chronic Formaldehyde-Mediated Impairments and Age-Related Dementia

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

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