DNA base flipping

Last updated

The DNA double helix with a cytosine base flipped out 180deg Dna-base-flipping.svg
The DNA double helix with a cytosine base flipped out 180°

DNA base flipping, or nucleotide flipping, is a mechanism in which a single nucleotide base, or nucleobase, is rotated outside the nucleic acid double helix. [1] This occurs when a nucleic acid-processing enzyme needs access to the base to perform work on it, such as its excision for replacement with another base during DNA repair. It was first observed in 1994 using X-ray crystallography in a methyltransferase enzyme catalyzing methylation of a cytosine base in DNA. Since then, it has been shown to be used by different enzymes in many biological processes such as DNA methylation, various DNA repair mechanisms, and DNA replication. It can also occur in RNA double helices [2] or in the DNA:RNA intermediates formed during RNA transcription.

Contents

DNA base flipping occurs by breaking the hydrogen bonds between the bases and unstacking the base from its neighbors. This could occur through an active process, where an enzyme binds to the DNA and then facilitates rotation of the base, or a passive process, where the base rotates out spontaneously, and this state is recognized and bound by an enzyme. It can be detected using X-ray crystallography, NMR spectroscopy, fluorescence spectroscopy, or hybridization probes.

Discovery

Base flipping was first observed in 1994 when researchers Klimasauskas, Kumar, Roberts, and Cheng used X-ray crystallography to view an intermediate step in the chemical reaction of a methyltransferase bound to DNA. [3] The methyltransferase they used was the C5-cytosine methyltransferase from Haemophilus haemolyticus (M. HhaI). This enzyme recognizes a specific sequence of the DNA (5'-GCGC-3') and methylates the first cytosine base of the sequence at its C5 location. [3] Upon crystallization of the M. HhaI-DNA complex, they saw the target cytosine base was rotated completely out of the double helix and was positioned in the active site of the M. HhaI. It was held in place by numerous interactions between the M. HhaI and DNA. [3]

The authors theorized that base flipping was a mechanism used by many other enzymes, such as helicases, recombination enzymes, RNA polymerases, DNA polymerases, and Type II topoisomerases. [3] Much research has been done in the years subsequent to this discovery and it has been found that base flipping is a mechanism used in many of the biological processes the authors suggest. [4] [5] [6]

Mechanism

Model of Entamoeba histolytica DNMT2. Demonstrates a base flipped out of the double helix and into the active site of a methyltransferase. Model of the EhMeth-DNA complex.jpg
Model of Entamoeba histolytica DNMT2. Demonstrates a base flipped out of the double helix and into the active site of a methyltransferase.

DNA nucleotides are held together with hydrogen bonds, which are relatively weak and can be easily broken. Base flipping occurs on a millisecond timescale [7] by breaking the hydrogen bonds between bases and unstacking the base from its neighbors. [8] The base is rotated out of the double helix by 180 degrees, [9] typically via the major groove, [5] and into the active site of an enzyme. This opening leads to small conformational changes in the DNA backbone [10] which are quickly stabilized by the increased enzyme-DNA interactions. [5] Studies looking at the free-energy profiles of base flipping have shown that the free-energy barrier to flipping can be lowered by 17 kcal/mol for M.HhaI in the closed conformation. [5]

There are two mechanisms of DNA base flipping: active and passive. [11] In the active mechanism, an enzyme binds to the DNA and then actively rotates the base, while in the passive mechanism a damaged base rotates out spontaneously first, then is recognized and bound by the enzyme. [8] Research has demonstrated both mechanisms: uracil-DNA glycosylase follows the passive mechanism [8] and Tn10 transposase follows the active mechanism. [12]

Furthermore, studies have shown that DNA base flipping is used by many different enzymes in a variety biological processes such as DNA methylation, various DNA repair mechanisms, RNA transcription and DNA replication. [4] [5] [6]

Biological processes

DNA modification and repair

A uracil residue flipped out of the DNA double helix and into the specificity pocket of Uracil DNA glycosylase Uracil base glycosidase.jpg
A uracil residue flipped out of the DNA double helix and into the specificity pocket of Uracil DNA glycosylase

DNA can have mutations that cause a base in the DNA strand to be damaged. To ensure genetic integrity of the DNA, enzymes need to repair any damage. There are many types of DNA repair. Base excision repair utilizes base flipping to flip the damaged base out of the double helix [5] and into the specificity pocket of a glycosylase which hydrolyzes the glycosidic bond and removes the base. [13] DNA glycosylases interact with DNA, flipping bases to determine a mismatch. An example of base excision repair occurs when a cytosine base is deaminated and becomes a uracil base. This causes a U:G mispair which is detected by Uracil DNA glycosylase. The uracil base is flipped out into the glycosylase active pocket where it is removed from the DNA strand. [14] Base flipping is used to repair mutations such as 8-Oxoguanine (oxoG) [15] and thymine dimers created by UV radiation. [13] [16]

Replication, transcription and recombination

DNA replication and RNA transcription both make use of base flipping. [5] DNA polymerase is an enzyme that carries out replication. It can be thought of as a hand that grips the DNA single strand template. [13] As the template passes across the palm region of the polymerase, the template bases are flipped out of the helix and away from the dNTP binding site. [17] During transcription, RNA polymerase catalyzes RNA synthesis. During the initiation phase, two bases in the -10 element flip out from the helix and into two pockets in RNA polymerase. These new interactions stabilize the -10 element and promote the DNA strands to separate or melt. [13] [18]

Base flipping occurs during latter stages of recombination. [19] RecA is a protein that promotes strand invasion [13] during homologous recombination. Base flipping has been proposed as the mechanism by which RecA can enable a single strand to recognize homology in duplex DNA. [20] Other studies indicate that it is also involved in V(D)J Recombination. [21]

DNA methylation

DNA molecule that is methylated on both strands on the center cytosine DNA methylation.jpg
DNA molecule that is methylated on both strands on the center cytosine

DNA methylation is the process in which a methyl group is added to either a cytosine or adenine. [22] This process causes the activation or inactivation of gene expression, thereby resulting in gene regulation in eukaryotic cells. DNA methylation process is also known to be involved in certain types of cancer formation. [23] [24] [25] In order for this chemical modification to occur, it is necessary that the target base flips out of the DNA double helix to allow the methyltransferases to catalyze the reaction. [5]

Target recognition by restriction endonucleases

Restriction endonucleases, also known as restriction enzymes are enzymes that cleave the sugar-phosphate backbone of the DNA at specific nucleotides sequences that are usually four to six nucleotides long. [26] Studies performed by Horton and colleagues have shown that the mechanism by which these enzymes cleave the DNA involves base flipping as well as bending the DNA and the expansion of the minor groove. [27] In 2006, Horton and colleagues, x-ray crystallography evidence was presented showing that the restriction endonuclease HinP1I utilizes base flipping in order to recognize its target sequence. This enzyme is known to cleave the DNA at the palindromic tetranucleotide sequence G↓CGC.

Experimental approaches for detection

X-ray crystallography

Workflow for solving the structure of a molecule by X-ray crystallography X ray diffraction.png
Workflow for solving the structure of a molecule by X-ray crystallography

X-ray crystallography is a technique that measures the angles and intensities of crystalline atoms in order to determine the atomic and molecular structure of the crystal of interest. Crystallographers are then able to produce and three-dimensional picture where the positions of the atoms, chemical bonds as well as other important characteristics can be determined.[ citation needed ] Klimasaukas and colleagues used this technique to observe the first base flipping phenomenon, in which their experimental procedure involved several steps: [3]

  1. Purification
  2. Crystallization
  3. Data Collection
  4. Structure determination and refinement

During purification, Haemophilus haemolyticus methyltransferase was overexpressed and purified using a high salt back-extraction step to selectively solubilize M.HhaI, followed by fast protein liquid chromatography (FPLC) as done previously by Kumar and colleagues. [28] Authors utilized a Mono-Q anion exchange column to remove the small quantity of proteinaceous materials and unwanted DNA prior to the crystallization step. Once M.HhaI was successfully purified, the sample was then grown using a method that mixes the solution containing the complex at a temperature of 16 °C and the hanging-drop vapor diffusion technique to obtain the crystals. Authors were then able to collect the x-ray data according to a technique used by Cheng and colleagues in 1993. [29] This technique involved the measurement of the diffraction intensities on a FAST detector, where the exposure times for 0.1° rotation were 5 or 10 seconds. For the structure determination and refinement, Klimasaukas and colleagues used the molecular replacement of the refined apo structure described by Cheng and colleagues in 1993 [29] where the search models X-PLOR, MERLOT, and TRNSUM were used to solve the rotation and translation functions. [30] [31] This part of the study involves the use of a variety of software and computer algorithms to solve the structures and characteristics of the crystal of interest.

NMR spectroscopy

NMR spectroscopy is a technique that has been used over the years to study important dynamic aspects of base flipping. This technique allows researchers to determine the physical and chemical properties of atoms and other molecules by utilizing the magnetic properties of atomic nuclei.[ citation needed ] In addition, NMR can provide a variety of information including structure, reaction states, chemical environment of the molecules, and dynamics. [32] [33] During the DNA base flipping discovery experiment, researchers utilized NMR spectroscopy to investigate the enzyme-induced base flipping of HhaI methyltransferase. In order to accomplish this experiment, two 5-fluorocytosine residues were incorporated into the target and the reference position with the DNA substrate so the 19F chemical shift analysis could be performed. Once the 19F chemical shift analysis was evaluated, it was then concluded that the DNA complexes existed with multiple forms of the target 5-fluorocytosine along the base flipping pathway. [34]

Fluorescence spectroscopy

Fluorescence spectroscopy is a technique that is used to assay a sample using a fluorescent probe. DNA nucleotides themselves are not good candidates for this technique because they do not readily re-emit light upon light excitation. [34] A fluorescent marker is needed to detect base flipping. 2-Aminopurine is a base that is structurally similar to adenine, but is very fluorescent when flipped out from the DNA duplex. [35] It is commonly used to detect base flipping and has an excitation at 305‑320 nm and emission at 370 nm so that it well separated from the excitations of proteins and DNA. Other fluorescent probes used to study DNA base flipping are 6MAP (4‑amino‑6‑methyl‑7(8H)‑pteridone) [36] and Pyrrolo‑C (3-[β-D-2-ribofuranosyl]-6-methylpyrrolo[2,3-d]pyrimidin-2(3H)-one). [37] [38] Time-resolved fluorescence spectroscopy is also employed to provide a more detailed picture of the extent of base flipping as well as the conformational dynamics occurring during base flipping. [39]

Hybridization probing

Hybridization probes can be used to detect base flipping. This technique uses a molecule that has a complementary sequence to the sequence you would like to detect such that it binds to a single-strand of the DNA or RNA. Several hybridization probes have been used to detect base flipping. Potassium permanganate is used to detect thymine residues that have been flipped out by cytosine-C5 and adenine-N6 methyltransferases. [40] Chloroacetaldehyde is used to detect cytosine residues flipped out by the HhaI DNA cytosine-5 methyltransferase (M. HhaI). [41]

A hybridization probe is added to a DNA molecule. LightCycler Probes.jpg
A hybridization probe is added to a DNA molecule.

See also

Related Research Articles

<span class="mw-page-title-main">DNA</span> Molecule that carries genetic information

Deoxyribonucleic acid is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of all known organisms and many viruses. DNA and ribonucleic acid (RNA) are nucleic acids. Alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for all known forms of life.

<span class="mw-page-title-main">Epigenetics</span> Study of DNA modifications that do not change its sequence

In biology, epigenetics is the study of heritable traits, or a stable change of cell function, that happen without changes to the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic mechanism of inheritance. Epigenetics usually involves a change that is not erased by cell division, and affects the regulation of gene expression. Such effects on cellular and physiological phenotypic traits may result from environmental factors, or be part of normal development. Epigenetic factors can also lead to cancer.

<span class="mw-page-title-main">5-Methylcytosine</span> Chemical compound which is a modified DNA base

5-Methylcytosine is a methylated form of the DNA base cytosine (C) that regulates gene transcription and takes several other biological roles. When cytosine is methylated, the DNA maintains the same sequence, but the expression of methylated genes can be altered. 5-Methylcytosine is incorporated in the nucleoside 5-methylcytidine.

<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA for the purpose of gene expression. Some segments of DNA are transcribed into RNA molecules that can encode proteins, called messenger RNA (mRNA). Other segments of DNA are transcribed into RNA molecules called non-coding RNAs (ncRNAs).

<span class="mw-page-title-main">CpG site</span> Region of often-methylated DNA with a cytosine followed by a guanine

The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands.

<span class="mw-page-title-main">DNA polymerase</span> Form of DNA replication

A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create two identical DNA duplexes from a single original DNA duplex. During this process, DNA polymerase "reads" the existing DNA strands to create two new strands that match the existing ones. These enzymes catalyze the chemical reaction

<span class="mw-page-title-main">DNA methyltransferase</span> Class of enzymes

In biochemistry, the DNA methyltransferase family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

<span class="mw-page-title-main">Helicase</span> Class of enzymes to unpack an organisms genes

Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleotidic backbone, separating two hybridized nucleic acid strands, using energy from ATP hydrolysis. There are many helicases, representing the great variety of processes in which strand separation must be catalyzed. Approximately 1% of eukaryotic genes code for helicases.

<span class="mw-page-title-main">Ribonucleotide</span> Nucleotide containing ribose as its pentose component

In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic monomeric building blocks for RNA. Deoxyribonucleotides, formed by reducing ribonucleotides with the enzyme ribonucleotide reductase (RNR), are essential building blocks for DNA. There are several differences between DNA deoxyribonucleotides and RNA ribonucleotides. Successive nucleotides are linked together via phosphodiester bonds.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">Base excision repair</span> DNA repair process

Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.

<span class="mw-page-title-main">Methyltransferase</span> Group of methylating enzymes

Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.

<span class="mw-page-title-main">Palindromic sequence</span> DNA or RNA sequence that matches its complement when read backwards

A palindromic sequence is a nucleic acid sequence in a double-stranded DNA or RNA molecule whereby reading in a certain direction on one strand is identical to the sequence in the same direction on the complementary strand. This definition of palindrome thus depends on complementary strands being palindromic of each other.

<span class="mw-page-title-main">DNA adenine methylase</span> Class of enzymes

DNA adenine methylase, (Dam) (also site-specific DNA-methyltransferase (adenine-specific), EC 2.1.1.72, modification methylase, restriction-modification system) is an enzyme that adds a methyl group to the adenine of the sequence 5'-GATC-3' in newly synthesized DNA. Immediately after DNA synthesis, the daughter strand remains unmethylated for a short time. It is an orphan methyltransferase that is not part of a restriction-modification system and regulates gene expression. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Pyrimidine dimer</span> Type of damage to DNA

Pyrimidine dimers represent molecular lesions originating from thymine or cytosine bases within DNA, resulting from photochemical reactions. These lesions, commonly linked to direct DNA damage, are induced by ultraviolet light (UV), particularly UVC, result in the formation of covalent bonds between adjacent nitrogenous bases along the nucleotide chain near their carbon–carbon double bonds, the photo-coupled dimers are fluorescent. Such dimerization, which can also occur in double-stranded RNA (dsRNA) involving uracil or cytosine, leads to the creation of cyclobutane pyrimidine dimers (CPDs) and 6–4 photoproducts. These pre-mutagenic lesions modify the DNA helix structure, resulting in abnormal non-canonical base pairing and, consequently, adjacent thymines or cytosines in DNA will form a cyclobutane ring when joined together and cause a distortion in the DNA. This distortion prevents DNA replication and transcription mechanisms beyond the dimerization site.

Epigenomics is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome. The field is analogous to genomics and proteomics, which are the study of the genome and proteome of a cell. Epigenetic modifications are reversible modifications on a cell's DNA or histones that affect gene expression without altering the DNA sequence. Epigenomic maintenance is a continuous process and plays an important role in stability of eukaryotic genomes by taking part in crucial biological mechanisms like DNA repair. Plant flavones are said to be inhibiting epigenomic marks that cause cancers. Two of the most characterized epigenetic modifications are DNA methylation and histone modification. Epigenetic modifications play an important role in gene expression and regulation, and are involved in numerous cellular processes such as in differentiation/development and tumorigenesis. The study of epigenetics on a global level has been made possible only recently through the adaptation of genomic high-throughput assays.

<span class="mw-page-title-main">Nucleic acid secondary structure</span>

Nucleic acid secondary structure is the basepairing interactions within a single nucleic acid polymer or between two polymers. It can be represented as a list of bases which are paired in a nucleic acid molecule. The secondary structures of biological DNAs and RNAs tend to be different: biological DNA mostly exists as fully base paired double helices, while biological RNA is single stranded and often forms complex and intricate base-pairing interactions due to its increased ability to form hydrogen bonds stemming from the extra hydroxyl group in the ribose sugar.

<span class="mw-page-title-main">Complementarity (molecular biology)</span> Lock-and-key pairing between two structures

In molecular biology, complementarity describes a relationship between two structures each following the lock-and-key principle. In nature complementarity is the base principle of DNA replication and transcription as it is a property shared between two DNA or RNA sequences, such that when they are aligned antiparallel to each other, the nucleotide bases at each position in the sequences will be complementary, much like looking in the mirror and seeing the reverse of things. This complementary base pairing allows cells to copy information from one generation to another and even find and repair damage to the information stored in the sequences.

Transgenerational epigenetic inheritance in plants involves mechanisms for the passing of epigenetic marks from parent to offspring that differ from those reported in animals. There are several kinds of epigenetic markers, but they all provide a mechanism to facilitate greater phenotypic plasticity by influencing the expression of genes without altering the DNA code. These modifications represent responses to environmental input and are reversible changes to gene expression patterns that can be passed down through generations. In plants, transgenerational epigenetic inheritance could potentially represent an evolutionary adaptation for sessile organisms to quickly adapt to their changing environment.

References

  1. ↑ Roberts, Richard J.; Cheng, Xiaodong (June 1998). "BASE FLIPPING". Annual Review of Biochemistry. 67 (1): 181–198. doi:10.1146/annurev.biochem.67.1.181. PMID   9759487.
  2. ↑ Reiter, Nicholas J.; Blad, Heike; Abildgaard, Frits; Butcher, Samuel E. (1 November 2004). "Dynamics in the U6 RNA Intramolecular Stem−Loop: A Base Flipping Conformational Change". Biochemistry. 43 (43): 13739–13747. doi:10.1021/bi048815y. PMID   15504036. S2CID   25391616.
  3. 1 2 3 4 5 Klimasauskas, Saulius; Kumar, Sanjay; Roberts, Richard J.; Cheng, Xiaodong (January 1994). "Hhal methyltransferase flips its target base out of the DNA helix". Cell. 76 (2): 357–369. doi:10.1016/0092-8674(94)90342-5. PMID   8293469. S2CID   23161543.
  4. 1 2 Brown, Tom. "Nucleic Acids Book". ATDBio. Retrieved 26 February 2014.
  5. 1 2 3 4 5 6 7 8 Huang, Niu; Banavali, Nilesh K.; MacKerell, Alexander D. (7 January 2003). "Protein-facilitated base flipping in DNA by cytosine-5-methyltransferase". Proceedings of the National Academy of Sciences. 100 (1): 68–73. Bibcode:2003PNAS..100...68H. doi: 10.1073/pnas.0135427100 . PMC   140885 . PMID   12506195.
  6. 1 2 Grubmüller, Helmut. "DNA Base Flipping". The Max Planck Institute for Biophysical Chemistry. Archived from the original on 4 February 2017. Retrieved 26 February 2014.
  7. ↑ Bouvier, Benjamin; Grubmüller, Helmut (August 2007). "A Molecular Dynamics Study of Slow Base Flipping in DNA using Conformational Flooding". Biophysical Journal. 93 (3): 770–786. Bibcode:2007BpJ....93..770B. doi:10.1529/biophysj.106.091751. PMC   1913169 . PMID   17496048.
  8. 1 2 3 Larivière, Laurent; Moréra, Solange (August 2004). "Structural Evidence of a Passive Base-flipping Mechanism for β-Glucosyltransferase". Journal of Biological Chemistry. 279 (33): 34715–34720. doi: 10.1074/jbc.M404394200 . PMID   15178685.
  9. ↑ Grosjean, Henri, ed. (2009). DNA and RNA modification enzymes: structure, mechanism, function and evolution. Molecular biology intelligence unit. Austin, Tex.: Landes Bioscience. ISBN   978-1-58706-329-9. OCLC   316421190. Archived from the original on 2014-04-07. Retrieved 2014-03-10.
  10. ↑ Giudice, Emmanuel; Várnai, Péter; Lavery, Richard (1 March 2003). "Base pair opening within B-DNA: free energy pathways for GC and AT pairs from umbrella sampling simulations". Nucleic Acids Research. 31 (5): 1434–1443. doi:10.1093/nar/gkg239. PMC   149832 . PMID   12595551.
  11. ↑ O'Neil, Lauren L. (2008). Base Flipping: Detection, Structures and Energetics (Thesis). University of Notre Dame. doi:10.7274/9306sx63d8n.
  12. ↑ Bischerour, Julien; Chalmers, Ronald (10 July 2009). "Base Flipping in Tn10 Transposition: An Active Flip and Capture Mechanism". PLoS ONE. 4 (7): e6201. Bibcode:2009PLoSO...4.6201B. doi: 10.1371/journal.pone.0006201 . PMC   2705183 . PMID   19593448.
  13. 1 2 3 4 5 Watson, James D.; Baker, Tania A.; Bell, Stephen P.; Gann, Alexander; Levine, Michael; Losick, Richard (2014). Molecular biology of the gene (Seventh ed.). Boston: Pearson. ISBN   978-0-321-76243-6.
  14. ↑ Krokan, Hans E; Drabløs, Finn; Slupphaug, Geir (16 December 2002). "Uracil in DNA – occurrence, consequences and repair". Oncogene. 21 (58): 8935–8948. doi:10.1038/sj.onc.1205996. PMID   12483510.
  15. ↑ Banerjee, Anirban; Yang, Wei; Karplus, Martin; Verdine, Gregory L. (March 2005). "Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA". Nature. 434 (7033): 612–618. Bibcode:2005Natur.434..612B. doi:10.1038/nature03458. PMID   15800616. S2CID   4426014.
  16. ↑ Fuxreiter, Monika; Luo, Ning; Jedlovszky, Pál; Simon, István; Osman, Roman (November 2002). "Role of Base Flipping in Specific Recognition of Damaged DNA by Repair Enzymes". Journal of Molecular Biology. 323 (5): 823–834. doi:10.1016/S0022-2836(02)00999-3. PMID   12417196.
  17. ↑ Patel, Premal H.; Suzuki, Motoshi; Adman, Elinor; Shinkai, Akeo; Loeb, Lawrence A. (May 2001). "Prokaryotic DNA polymerase I: evolution, structure, and "base flipping" mechanism for nucleotide selection". Journal of Molecular Biology. 308 (5): 823–837. doi:10.1006/jmbi.2001.4619. PMID   11352575.
  18. ↑ Lim, Heon Man; Lee, Hee Jung; Roy, Siddhartha; Adhya, Sankar (18 December 2001). "A "master" in base unpairing during isomerization of a promoter upon RNA polymerase binding". Proceedings of the National Academy of Sciences. 98 (26): 14849–14852. Bibcode:2001PNAS...9814849L. doi: 10.1073/pnas.261517398 . PMC   64947 . PMID   11734629.
  19. ↑ Voloshin, Oleg N.; Camerini-Otero, R.Daniel (September 2004). "Synaptic Complex Revisited". Molecular Cell. 15 (6): 846–847. doi: 10.1016/j.molcel.2004.09.010 . PMID   15383274.
  20. ↑ Folta-Stogniew, Ewa; O'Malley, Shawn; Gupta, Ravindra; Anderson, Karen S.; Radding, Charles M. (September 2004). "Exchange of DNA Base Pairs that Coincides with Recognition of Homology Promoted by E. coli RecA Protein". Molecular Cell. 15 (6): 965–975. doi: 10.1016/j.molcel.2004.08.017 . PMID   15383285.
  21. ↑ Bischerour, Julien; Lu, Catherine; Roth, David B.; Chalmers, Ronald (1 November 2009). "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". Molecular and Cellular Biology. 29 (21): 5889–5899. doi:10.1128/MCB.00187-09. PMC   2772739 . PMID   19720743.
  22. ↑ Klose, Robert J.; Bird, Adrian P. (February 2006). "Genomic DNA methylation: the mark and its mediators". Trends in Biochemical Sciences. 31 (2): 89–97. doi:10.1016/j.tibs.2005.12.008. ISSN   0968-0004. PMID   16403636.
  23. ↑ Nakao, Mitsuyoshi (October 2001). "Epigenetics: interaction of DNA methylation and chromatin". Gene. 278 (1–2): 25–31. doi:10.1016/s0378-1119(01)00721-1. PMID   11707319.
  24. ↑ Plass, Christoph; Soloway, Paul D (1 January 2002). "DNA methylation, imprinting and cancer". European Journal of Human Genetics. 10 (1): 6–16. doi: 10.1038/sj.ejhg.5200768 . PMID   11896451.
  25. ↑ Esteller, Manel; Herman, James G. (January 2002). "Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours". The Journal of Pathology. 196 (1): 1–7. doi:10.1002/path.1024. PMID   11748635. S2CID   35380651.
  26. ↑ "Biology and Activity of Restriction Endonucleases". Archived from the original on 2014-04-18. Retrieved 2014-04-03.
  27. ↑ Horton, John R.; Zhang, Xing; Maunus, Robert; Yang, Zhe; Wilson, Geoffrey; Roberts, Richard; Cheng, Xiaodong (2006). "DNA Nicking by HinP1I Endonuclease: Bending, Base Flipping and Minor Groove Expansion". Nucleic Acids Research. 34 (3): 939–948. doi:10.1093/nar/gkj484. PMC   1363774 . PMID   16473850.
  28. ↑ Kumar, Sanjay; Cheng, Xiaodong; Pflugrath, James W.; Roberts, Richard J. (15 September 1992). "Purification, crystallization, and preliminary x-ray diffraction analysis of an M.HhaI-AdoMet complex". Biochemistry. 31 (36): 8648–8653. doi:10.1021/bi00151a035. PMID   1390649.
  29. 1 2 Cheng, Xiaodong; Kumar, Sanjay; Posfai, Janos; Pflugrath, James W.; Roberts, Richard J. (July 1993). "Crystal structure of the Hhal DNA methyltransferase complexed with S-adenosyl-l-methionine". Cell. 74 (2): 299–307. doi:10.1016/0092-8674(93)90421-l. PMID   8343957. S2CID   54238106.
  30. ↑ Brünger, Axel T. (1992). X-PLOR, Version 3.1: a system for X-ray crystallography and NMR. New Haven: Yale University Press. ISBN   9780300054026.
  31. ↑ Fitzgerald, P. M. D. (1 June 1988). "MERLOT, an integrated package of computer programs for the determination of crystal structures by molecular replacement". Journal of Applied Crystallography. 21 (3): 273–278. doi:10.1107/s0021889887012299.
  32. ↑ Guéron, Maurice; Leroy, Jean-Louis (1995). "Studies of base pair kinetics by NMR measurement of proton exchange". Methods in Enzymology. 261: 383–413. doi:10.1016/s0076-6879(95)61018-9.
  33. ↑ Leijon, M.; Graslund, A. (1992). "Effects of sequence and length on imino proton-exchange and basepair opening kinetics in DNA oligonucleotide duplexes". Nucleic Acids Res. 20 (20): 5339–5343. doi:10.1093/nar/20.20.5339. PMC   334339 . PMID   1331987.
  34. 1 2 Klimašauskas, Saulius; Liutkevičiūtė, Zita (2009). "Experimental Approaches to Study DNA Base Flipping". In Grosjean, Henri (ed.). DNA and RNA modification enzymes: structure, mechanism, function and evolution. Austin, Texas: Landes Bioscience. ISBN   978-1-58706-329-9.
  35. ↑ Holz, B (15 February 1998). "2-Aminopurine as a fluorescent probe for DNA base flipping by methyltransferases". Nucleic Acids Research. 26 (4): 1076–1083. doi:10.1093/nar/26.4.1076. PMC   147370 . PMID   9461471.
  36. ↑ Yang, Kongsheng; Matsika, Spiridoula; Stanley, Robert J. (1 September 2007). "6MAP, a Fluorescent Adenine Analogue, Is a Probe of Base Flipping by DNA Photolyase". The Journal of Physical Chemistry B. 111 (35): 10615–10625. doi:10.1021/jp071035p. PMID   17696385.
  37. ↑ Yang, Kongsheng; Stanley, Robert J. (May 2008). "The Extent of DNA Deformation in DNA Photolyase– Substrate Complexes: A Solution State Fluorescence Study". Photochemistry and Photobiology. 84 (3): 741–749. doi:10.1111/j.1751-1097.2007.00251.x. PMID   18086248. S2CID   44506405.
  38. ↑ Berry, David A.; Jung, Kee-Yong; Wise, Dean S.; Sercel, Anthony D.; Pearson, William H.; Mackie, Hugh; Randolph, John B.; Somers, Robert L. (March 2004). "Pyrrolo-dC and pyrrolo-C: fluorescent analogs of cytidine and 2′-deoxycytidine for the study of oligonucleotides". Tetrahedron Letters. 45 (11): 2457–2461. doi:10.1016/j.tetlet.2004.01.108.
  39. ↑ Neely, Robert K.; Tamulaitis, Gintautas; Chen, Kai; Kubala, Marta; Siksnys, Virginijus; Jones, Anita C. (November 2009). "Time-resolved fluorescence studies of nucleotide flipping by restriction enzymes". Nucleic Acids Research. 37 (20): 6859–6870. doi:10.1093/nar/gkp688. PMC   2777440 . PMID   19740769.
  40. ↑ Serva, Saulius; Weinhold, Elmar; Roberts, Richard J.; Klimasauskas, Saulius (1 August 1998). "Chemical display of thymine residues flipped out by DNA methyltransferases". Nucleic Acids Research. 26 (15): 3473–3479. doi:10.1093/nar/26.15.3473. PMC   147733 . PMID   9671807.
  41. ↑ Daujotyte, D.; Liutkeviciute, Z.; Tamulaitis, G.; Klimasauskas, S. (15 April 2008). "Chemical mapping of cytosines enzymatically flipped out of the DNA helix". Nucleic Acids Research. 36 (10): e57 –e57. doi:10.1093/nar/gkn200. PMC   2425465 . PMID   18450817.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.