Making the Bend: DNA Tertiary Structure and  Protein-DNA Interactions

Harteis, Sabrina; Schneider, Sabine

doi:10.3390/ijms150712335

Cited by 104 publications

(99 citation statements)

References 167 publications

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“…Moreover, the sequence also influences the stiffness of DNA, which is directly linked to the base pair rigidity 22. A/T rich sequences have a lower persistence length and are therefore more bendable than G/C rich sequences 23.…”

Section: Resultsmentioning

confidence: 99%

Determination of DNA Hypermethylation Using Anti‐cancer Drug‐Temozolomide

2015

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[a] GokÅeS erindere, [a] and Melike Ozder [a] 1IntroductionTe mozolomide( TMZ) is an ew class of imidazotetrazinone derivatives and an oral alkylating agent approved by the Food and Drug Administration (FDA) for the treatment of glioblastoma multiform and recurrent anaplastic astrocytoma [1].T MZ enters the cerebrospinal fluid and readily crosses the bloodÀbrain barrier so it is of special interest in central nervous systems tumors. TMZ contains three adjacent nitrogen atoms and presents unique physicochemical properties and much greater anti-cancer activity than the previously synthesized bicyclic triazenes, whichc ontaino nly two adjacent nitrogen atoms [2].TMZ is substantially stable under acid conditions. This means that it can be administeredo rallyi nc apsules.T he rate of degradation increases rapidly on passing through neutralt ob asic pH [3].U nder physiologicalc onditions, TMZ is rapidly hydrolyzed and convertedi nto activem etabolite 5-(3-methyltriazeno) imidazole-4-carboxamide (MTIC) without the need for enzymatic demethylation in the liver. TMZi sn ot active until it is converted to MTIC at physiologic pH. Thes pontaneous conversiono fT MZ to MTIC is initiated by the effecto fw ater at the highly electropositive C4 position of TMZ. This activity opens the ring,releases CO 2 and generates MTIC.MTIC is then hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC) [4].A IC is additionally converted to am ethyldiazonium cation that is capable of alkylating DNAf rom the O6 and N7 positions on guanine and N3 positiono na denine.T he attack causes the transfer of am ethyl groupf rom the ion to form amethylated-DNAa dduct.Alkylation/methylationa tt he O6 position of guanine leads to mispairing with thymine,D NA double-strand breaks and cell cycle arrest and eventual apoptosis of the affected cell [3,5].T MZ showsi ts anti-cancer characteristics by methylationo fD NA.D NA methylation (addition of am ethyl groupt ot he 5 carbon of cytosine base)i sa n epigenetic alteration and ap romising biomarker for detection of variousc ancer types including breast [6],l ung [7],p rostate [8] and ovarian cancer [9].F or instance,h ypermethylation of the CpG islands (region rich in cytosine and guanineb ases)a tt he promoter region of Glutathione S-Transferase P-1 (GSTP-1) gene has been widely introduced as one of the promising biomarker of the prostate cancer due to being presenti nn early 90 %o f prostate cancer cases but not in normalp rostate tissues [10]. GSTP-1 is mainly related to eliminationo fp otentially toxic compounds in the cell. These functions of GSTP-1 help protect cells from metabolites of carcinogens and thus any alteration of this gene could result in DNAd amage.Abstract:A ne lectrochemicald rug-DNAb iosensor was developed for the detection of interaction between the anti-cancer drug, Te mozolomide (TMZ), and DNAs equences by using Differential Pulse Voltammetry at the graphite electrode surfaces.T MZ is ap ro-drug anda na lkylatinga gent thatc rosses the blood-brain barrier,s oi ti s mainly used for bra...

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Section: Resultsmentioning

confidence: 99%

Determination of DNA Hypermethylation Using Anti‐cancer Drug‐Temozolomide

2015

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“…Future studies may find more basic genomic features that could predict the XR-seq coverage or similar empirical measurements of mutability. These may include factors such as: (i) yet-unknown proteins bound to the DNA; (ii) tertiary structure of the DNA helix (Harteis and Schneider, 2014) (which can influence binding of such proteins); (iii) a combination of the two (a recent study (Mao et al, 2018) suggests that the binding of ETS transcription factors rotates adjacent pyrimidines into a more favorable conformation to form a cyclobutane dimer between adjacent C5-C6 bonds); (iv) local chromatin structure (which could affect gene expression or accessibility to mutagens or repair enzymes); or (v) sequence-specific polymerase error modes that our datasets are not yet powered to detect.…”

Section: Discussionmentioning

confidence: 99%

Passenger Hotspot Mutations in Cancer

Hess

Bernards

Kim

et al. 2019

Preprint

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Hotspots, or mutations that recur at the same genomic site across multiple tumors, have been conventionally interpreted as strong universal evidence of somatic positive selection, unequivocally pinpointing genes driving tumorigenesis. Here, we demonstrate that this convention is falsely premised on an inaccurate statistical model of background mutagenesis. Many hotspots are in fact passenger events, recurring at sites that are simply inherently more mutable rather than under positive selection, which current background models do not account for. We thus detail a log-normal-Poisson (LNP) background model that accounts for variation in site-specific mutability in a manner consistent with models of mutagenesis, use this model to show that the tendency to generate passenger hotspots pervades all common mutational processes, and apply it to a ⇠10, 000 patient cohort from The Cancer Genome Atlas to nominate driver hotspots with far fewer false positives compared to conventional methods. As the biomedical community faces critical decisions in prioritizing putative driver mutations for deep experimental characterization to assess therapeutic potential, we offer our findings as a guide to avoid wasting valuable scientific resources on passenger hotspots. Identification of significantly mutated regions across cancer types highlights a rich landscape of functional molecular alterations. Nat. Genet., 48 (2):117-125, February 2016. Hanadi Baeissa, Graeme Benstead-Hume, Christopher J Richardson, and Frances M G Pearl. Identification and analysis of mutational hotspots in oncogenes and tumour suppressors. Oncotarget, 8(13):21290-21304, 2017. F Bahram, N von der Lehr, C Cetinkaya, and L G Larsson. c-myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasomemediated turnover. Blood, 95(6):

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“…Specifically, it has been reported that Z-DNA is related to both transcriptional activation 41,42 and inhibition 43,44 . Mechanistically, this change in structure is thought to be coupled to transcription by the recruitment of transcription factors, such as PolII, for enhancement, or the direct blockade of the transcriptional machinery leading to PollI stalling during inhibition 37,39,[45][46][47] .…”

Section: Discussionmentioning

confidence: 99%

Dynamic DNA structure states interact with the RNA editing enzyme ADAR1 to modulate fear extinction memory

Zhao

et al. 2019

Preprint

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RNA modification has recently emerged as an important mechanism underlying gene diversity linked to behavioral regulation. The conversion of adenosine to inosine by the ADAR family of enzymes is a particularly important RNA modification as it impacts the physiological readout of protein-coding genes. However, not all variants of ADAR appear to act solely on RNA. ADAR1 binds directly to DNA when it is in a non-canonical, left handed, "Z" conformation, but little is known about the functional relevance of this interaction. Here we report that ADAR1 binds to Z-DNA in an activity-dependent manner and that fear extinction learning leads to increased ADAR1 occupancy at DNA repetitive elements, with targets adopting a Z-DNA structure at sites of ADAR1 recruitment.Knockdown of ADAR1 leads to an inability to modify a previously acquired memory trace and this is associated with a concomitant change in DNA structure and a decrease in RNA editing. These findings suggest a novel mechanism of learning-induced gene regulation whereby ADAR1 physically interacts with Z-DNA in order to mediate its effect on RNA, and both are required for memory flexibility following fear extinction learning.

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Making the Bend: DNA Tertiary Structure and Protein-DNA Interactions

Cited by 104 publications

References 167 publications

Determination of DNA Hypermethylation Using Anti‐cancer Drug‐Temozolomide

Determination of DNA Hypermethylation Using Anti‐cancer Drug‐Temozolomide

Passenger Hotspot Mutations in Cancer

Dynamic DNA structure states interact with the RNA editing enzyme ADAR1 to modulate fear extinction memory

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