User:Amontei2/sandbox

The five pillars of Wikipedia

 * 1) Wikipedia is an encyclopedia - It is not intended for advertising products and people, it is not a web directory or a dictionary
 * 2) Always use a neutral point of view when adding content to Wikipedia. Editor’s point of view or a biased content do not belong on Wikipedia. Make sure to show always both sides of the information and let the reader decide.
 * 3) Wikipedia is a free content page in which anyone is free to edit/modify, use and contribute to any information added.
 * 4) Editors should always treat others with respect and assume good faith (in which the other editor wants to contribute to the topic as much as you do). When a discussion arises, address the topic calmly and with respect.
 * 5) Wikipedia has policies and guideline that are not set in stone. Rules and guidelines can be changed in order to improve on different aspects of the site. Be bold but make sure to not be reckless. Finally, do not be afraid of making mistakes as others will help you with the content respectfully.

Summary of characteristics of target article
The goal from our course is substantially contribute to Wikipedia by editing a stub on the subject of interest selected previously by our instructor. The goal of this project is to start from a stub and increase the quality level to a B or a GA article. What are the characteristics of such entries? A good article contains the characteristics below:


 * 1: It is well written, where the correct spelling and grammar is used and the copyright laws are correctly followed.


 * 2: It is verifiable, where the appropriate research is easily founds, it contains the appropriate citation labeled, and it does not contain original research.
 * 3: It contains a broad coverage where the main points are addressed.


 * 4: It is completely neutral, where personal opinion and/or biased comments are made. Remember: The five Pillars of Wikipedia when addressing these points.


 * 5: It contains stable information where a content dispute can be avoided.


 * 6: Finally, a good article should contain illustrations of the topic where the appropriate citation and copyright status is always available.

Short Paragraph
Mutations are classified as changes in the nucleotide sequence of the genetic code. There are a variety of mutations, but for the purpose of this post, point mutations will be discussed. As per our textbook, there are three kinds of point mutations. The first mutation listed is the missense mutation. This type of point mutation refers to an alteration of the nucleotide sequence that replaces a codon specific to an amino acid for another codon that codes for a completely different amino acid. One classic example of this type of mutation is the disease sickle-cell anemia, where the glutamate 6 in the Human β-globin locus subunit of hemoglobin is replaced with a Valine. Another type of point mutation is Nonsense Mutation,also know as stop codon mutation. It refers to an alteration on the nucleotide sequence that causes a change to a chain-termination codon. This is a very drastic effect, which could eventually lead to a very short polypeptide translation. Last but not least,frameshift mutation is another type of point mutations mentioned in our text. This type of mutation refers to insertions or deletions of one or more nucleotides that causes the reading frame to be shifted. This shift could potentially result in the translation of a completely different polypeptide. This is due to the fact that the genetic code is translated sequentially, three bases at a time, and if, for example, one nucleotide is inserted into the genome it would cause the frame to shift by one nucleotide. However, if three nucleotides are added, an extra amino acid would be translated with no major affect on the overall frame. . There is a substantial amount of work being done to study different effects of these mutations in the human body as many of them are related to many diseases today.

Definition

 * "The ability of a base to protrude from the double helix in an extrahelical configuration. When extruded from the helix, the base can sit in the catalytic cavity of enzymes that methylate bases or remove damaged bases." Source: Molecular Biology of the Gene, 7th ed definition, eBook Glossary
 * "Base flipping is the phenomenon whereby a base in normal B-DNA is swung completely out of the helix into an extrahelical position. It was discovered in 1994 when the first co-crystal structure was reported for a cytosine-5 DNA methyltransferase binding to DNA." Base flipping.  www.ncbi.nlm.nih.gov/pubmed/9759487

First Discovered

 * Klimasauskas, Saulius, Sanjay Kumar, Richard Roberts, and Xiaodong Cheng. "Hhal Methyltransferase Flips Its Target Base Out of the DNA Helix." Cell Press 76.2 (1994): 357-369. Web. 3 Mar. 2014. .
 * This article was the first demonstration of base flipping using x-ray crystallography.

DNA methylation

 * Holz, Birgit, and Elmar Weinhold. "2-Aminopurine as a Fluorescent Probe for DNA Base Flipping by Methyltransferases." Nucleic Acids Research 26.4 (1998): 1076-1083. Web. 2 Mar. 2014. .
 * This article investigates whether duplex oligodeoxynucleotides containing the fluorescent base analogue 2-aminopurine can be used to sense DNA base flipping. Authors used methyltransferase M.Hhal to demonstrate that “duplex oligodeoxynucleotides containinf 2-aminopurine at the target site can serve as fluorescence probes for base flipping”.


 * Arita, Kyohei, Mariko Aryoshi, Hidehito Tochio, Yusuke Nakamura, and Masashiro Shirakawa. "Recognition of Hemi-methylated DNA by the SRA Protein UHRF1 by a Base-flipping Mechanism." Nature 455(2008): 818-821. Web. 2 Mar. 2014. .
 * In this article author report the crystal structures of the SRA domain in free and hemi-methylated DNA-bound states. “The complex structure suggests that the successive flip out of the pre-existing methylated cytosine and the target cytosine to be methylated is associated with the coordinated transfer of the hemi-methylated CpG site from UHRF1 to Dnmt1.”


 * Matje, Douglas, Hongju Zhou, Darren Smith, Robert Neely, David Dryden, Anita Jones, Frederick Dahlquist, and Noberto Reich. "Enzyme-Promoted Base Flipping Controls DNA Methylation Fidelity." Biochemistry 52.10 (2013): 1677-1685. Web. 2 Mar. 2014. .


 * Bianchi, Caterina, and Ronen Zangi. "Dual Base-flipping of Cytosines in a CpG Dinucleotide Sequence." Biophysical Chemistry 187(2014): 14-22. Web. 2 Mar. 2014. 
 * This paper suggests that the extra-helical conformation of the methyl-cytosine recognized by UHRF1 can facilitate the base-flipping process of the target cytosine to be methylated by Dnmt1.

DNA repair mechanisms

 * WP:base excision repair
 * wp:glycosylase
 * "A nucleotide-flipping mechanism from the structure of human uracil-DNA glycosylase bound to DNA", http://www.ncbi.nlm.nih.gov/pubmed/8900285

Transcription

 * "Strong minor groove base conservation in sequence logos implies DNA distortion or base flipping during replication and transcription initiation" http://nar.oxfordjournals.org/content/29/23/4881.full.pdf+html


 * Textbook, page 438, "two bases in the non-template strand of the -10 element (A11 and T7) flip out from their base-stacking interactions and instead insert into pockets with the sigma protein where they make more favorable interactions."

Replication

 * Patel, Premal, Motoshi Suzuki, Elinor Adman, Akeo Shinkai, and Pawrence Loeb. "Prokaryotic DNA Polymerase I: Evolution, Structure, and “base Flipping” Mechanism for Nucleotide Selection." Journal of Molecular Biology 308.5 (2001): 823-827. Web. 2 Mar. 2014. .
 * In this article authors propose a mechanism for “flipping” of the complementary template base to enhance interactions with the incoming nucleotide substrate during DNA synthesis.

Other process

 * Matje, Douglas, Cody Krivacic, Frederick Dahlquist, and Norbert Reich. "Distal Structural Elements Coordinate a Conserved Base Flipping Network." Biochemistry 52.10 (2013): 1669-1676. Web. 2 Mar. 2014. .


 * Cheng, Xiaodong, and Robert Blumenthal. "Cytosines Do It, Thymines Do It, Even Pseudouridines Do It—Base Flipping by an Enzyme That Acts on RNA." Cell Press 10.2 (2002): 127-129. Web. 5 Mar. 2014. .
 * Authors showed the structure of a tRNA pseudouridine synthase and its relationship with base flipping. They demostrated that the target uridine flipped out from the tRNA; therefore, confirming that base flipping is not limited to enzymes that act on DNA.


 * Horton, John, Gary Ratner, Nilesh Banavali, Niu Huang, Yongseok Choi, Martin Maier, Victor Marquez, Alexander MacKerell Jr., and Xiaodong Cheng. "Caught in the Act: Visualization of an Intermediate in the DNA Base-flipping Pathway Induced by HhaI Methyltransferase." Nucleic Acid Research 32.13 (2004): 3877-3886. Web. 5 Mar. 2014. .
 * Authors discuss the possibility of the "south-constrained pseudosugar mimicking a transition state in the phosphodiester and sugar moieties that occurs during DNA base flipping in the presence of M.HhaI".


 * Banavali, N. "Analyzing the Relationship Between Single Base Flipping and Strand Slippage Near DNA Duplex Termini." J Phys Chem B 117.46 (2013): 14320-14328. Web. 5 Mar. 2014. .
 * " Author talks about the relationship of base flipping and insertion-deletion (indel) mutations that are caused by strand slippage between pairing primer and template strands during nucleic acid strand extension.


 * Banavali, Nilesh. "Partial Base Flipping Is Sufficient for Strand Slippage Near DNA Duplex Termini." Journal of American Chemical Society 135.22 (2013): 8274-8282. Web. 2 Mar. 2014. .
 * This study showed that "restrained and unrestrained molecular dynamics simulations, carried out using multiple nucleic acid force fields, are used to demonstrate that partial base-flipping can be sufficient for strand slippage at DNA duplex termini".


 * "Base Flipping in V(D)J Recombination: Insights into the Mechanism of Hairpin Formation, the 12/23 Rule, and the Coordination of Double-Strand Breaks" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772739/

Experimental approaches

 * https://www.landesbioscience.com/pdf/04GrosjeanKlimasauskas.pdf
 * "Time-resolved fluorescence studies of nucleotide flipping by restriction enzymes" http://nar.oxfordjournals.org/content/37/20/6859.full
 * using fluorescence spectroscopy to investigate the nucleotide flipping mechanism

Good background

 * http://www.atdbio.com/content/54/Base-flipping#Further-reading
 * http://www.annualreviews.org.proxy1.library.jhu.edu/doi/pdf/10.1146/annurev.biochem.67.1.181
 * http://books.google.com/books?id=Zm26mDpW3TIC&pg=PA7&lpg=PA7&dq=dna+repair+mechanism+base+flipping&source=bl&ots=UVadDm93io&sig=y99dtOHQedqsOP3qIs0uOQPr1hE&hl=en&sa=X&ei=BOUXU7XqPKTJ0wHLuoCoCw&ved=0CI4BEOgBMAw#v=onepage&q=dna%20repair%20mechanism%20base%20flipping&f=false

Dynamics of base flipping
1. http://www.mpibpc.mpg.de/276493/paper_moleculare_dynamics_study.pdf
 * “Base flipping was found to occur on a millisecond timescale, compatible with the energy penalty involved with the breaking of Watson and Crick hydrogen bonds and the unstacking of the target base relative to its intrastrand neighbors.”

2. "Molecular dynamics simulations and free energy calculations of base flipping in dsRNA", http://rnajournal.cshlp.org/content/11/5/609.full.pdf+html

3. "Base pair opening within B‐DNA: free energy pathways for GC and AT pairs from umbrella sampling simulations",  http://nar.oxfordjournals.org/content/31/5/1434.long
 * major groove opening is clearly favored for the larger purine bases
 * conformational consequences of base opening
 * hydrogen bonding in base pair is broken
 * “opening can be produced with only small conformational changes in the DNA backbones”

4. M. Ashley Spies and Richard L. Schowen, “The Trapping of a Spontaneously “Flipped-Out” Base from Double Helical Nucleic Acids by Host−Guest Complexation with β-Cyclodextrin:  The Intrinsic Base-Flipping Rate Constant for DNA and RNA”,  J. Am. Chem. Soc., 2002, 124 (47), pp 14049–14053, DOI: 10.1021/ja012272n, http://pubs.acs.org/doi/abs/10.1021/ja012272n
 * In vitro rate constant for spontaneous “flipping out” of a base from within the duplex structure of the nucleic acids = (3.5 ± 0.5) × 10-3 s-1 at 61 °C (DNA) and at 50 °C (RNA)

5. Huang N1, Banavali NK, MacKerell AD Jr., “Protein-facilitated base flipping in DNA by cytosine-5-methyltransferase.” Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):68-73. Epub 2002 Dec 27.,   doi: 10.1073/pnas.0135427100, http://www.pnas.org/content/100/1/68.full
 * In water, base flipping has large energetic penalties of 18 kcal/mol or more
 * But in active-site loop of M.HhaI, major groove barrier to flipping now being 0.4 kcal/mol
 * Preferred pathway for base flipping is via the major groove
 * M.HhaI “does facilitate the base-flipping process, leading to negligible free-energy barriers to flipping. This facilitation is caused by destabilization of the double-helical DNA conformation through protein–DNA interactions followed by interactions of the flipping base with the protein matrix, stabilizing the partially flipped states. Upon attaining the fully flipped state, the presence of the coenzyme is shown to stabilize this conformation by increasing the number of protein–DNA interactions and decreasing the solvent exposure of the DNA.”

6. Larivière L1, Moréra S. “Structural evidence of a passive base-flipping mechanism for beta-glucosyltransferase.” J Biol Chem. 2004 Aug 13;279(33):34715-20. http://www.jbc.org/content/279/33/34715.long
 * “Whether rotation is initiated by an active process in which the enzyme rotates the sugar-phosphate backbone or a passive one in which the enzyme binds to a spontaneously flipped-out base in a transient conformation remains unclear”
 * “BGT is now the first example of an enzyme that clearly plays a passive role in the base-flipping process.”

7. Julien Bischerour,     Ronald Chalmers,” Base Flipping in Tn10 Transposition: An Active Flip and Capture Mechanism”    Published: July 10, 2009    DOI: 10.1371/journal.pone.0006201, http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0006201
 * “We show that base flipping in Tn10 transposition is not a passive reaction in which a spontaneously flipped base is captured and retained by the protein. Rather, it is driven in part by a methionine probe residue that helps to force the flipped base from the base stack.”

Images
http://maptest.rutgers.edu/drupal/?q=node/58 (I have contacted the website to make sure we could use the image without any copyright issues - therefore, this image is pending) Amontei2 (talk) 02:23, 7 March 2014 (UTC)

https://commons.wikimedia.org/wiki/File:Dna-base-flipping.svg

Draft Outline

 * Lead/Define
 * Discovery
 * Mechanism
 * 1. Biochemistry: large energetic cost breaking H-bonds & base-stacking disruptions
 * 2. dynamics
 * 3. Active (bind & flip at same time) vs. Passive (flip, then bind)


 * Biological Processes
 * 1. DNA modification and repair
 * 2. Replication, Transcription, & Recombination
 * 3. DNA Methylation
 * 4. Sequence Specific target recognition by restriction endonucleases


 * Experimental Approaches
 * 1. X-ray crystallography
 * 2. NMR spectroscopy
 * 3. Fluorescent spectroscopy
 * 4. Chemical probing


 * Systems???
 * 1. Hha1 DNA Methyltransferase
 * 2. Uracil-DNA glycosylase