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176 Cards in this Set
- Front
- Back
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DNA
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Stands for deoxyribonucleic acid, has 3' OH and 5' phosphate group, has base on C-1 carbon of ribose sugar, joined by N-1 linkage on pyrimidines (Cytosine and Thymine), N-9 linkage for purines (Adenine and Guanine)
Remember: AG POO ON THE 9, CUT THE PY ON THE 1 |
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DNA backbone
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Negatively charged phosphates, alternating sugar phosphate backbone
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Nucleoside
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Ribose and the Base
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Nucleotide
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Ribose, base, and triphosphate
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Oligonucleotides
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small groups of 5-50 nuclelotides
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DNA structure
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anti-parallel (5'-3' 3'-5'), sugar phosphate backbones are on outside, hydrophobic bases or on the inside.
Distance between each base pair is 3.4 Angstroms. One complete turn per helix is 10 bp. -Highly charged at physiologic pH due to phosphate groups. A=T, G triple bonds with C! |
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DNA topology
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Whole DNA strands may be overwound or underwound, twisted around its own axis, it is referred as supercoiled DNA
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Positive supercoiling
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Twisted same direction
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Negative supercoling
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Direction opposite ot the intrinsic turns of a right handed double helix
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Topo I
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Topoisomerase I cleaves one strand of DNA
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Type II topoisomerase
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Cleaves both strands
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m-AMSA
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inhibits type II topoisomerase
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campotheican
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inactivates topo I
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Z-DNA
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left handed double helix, alternating purines and pyrimidines
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DNA bending
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inherently bent (adenine repeats), ex: bending of DNA around histones, can bring distant sites together
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Triplex DNA
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polypurine or polypyrimidine tracts form triple helical DNA
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Melting and reannealing of complementary strands
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Tm depends on AT and GC onctent, higher GC content means higher melting point of the DNA
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Re-annealing
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Highly specific and will take place if base sequences are complementary, concept exploited in probes
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Eukaryotic DNA
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3 x 10^9 bp, approximately 30,000 genes, sequencing due to the HGP
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Functional Genes
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Only a small portion of our genome 1-2% encode for functional genes
Genes can be associated into gene families, (ex: B globin gene cluster) Genes encoding abundant products are often trandemly repeated and clustered together. We lost the genes for vitamin synthesis |
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Junk DNA
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95% probably "junk"
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Pseudogenes
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Closely related to functional genes but due to deletions insertions and point mutations they no longer code for normal gene products.
Furthermore, processed pseudogenes are formed when reverse transcripts of RNA molecules are inserted into organisms genome |
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Proviruses
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DNA copies of retroviruses in the genomes
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Repetitive DNA sequences
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Transposable Elements
SSR Satellite Sequences |
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Transposable elements
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40% of genome made due to reverse transcription
Consist of LINES, SINES (not tandemly repeated!), and transposase elements |
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SINES
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Alu family (280 nts), 1 every 5 kb. 10% human DNA consists of ALU repeats
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LINES
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at least 500 nt, 20% abundant in genome, LINE elements encode reverse transcriptase
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Transposable elements
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encode their own transposase, represent about 3% of human genome
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SSRS:
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comprise about 3% of hsumang enome, approximately1 SSR per every 2 kb
Microsatellites (2-5 bp) tandemly repeated: mean array size is 100 Minisatellites (14-500 bp)- minisatellites (VNTR's), can serve as genetic markers! |
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Satellite sequences
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Repeat unit of satellite sequence varies greatly, clusters in non-transcribed regions: telomeres
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Telomeres
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Found at the ends of every human chromosome,, TTAGGG, tandem arrays shortening of telemores as a mitotic clock
Telomerase: is inactive in non-proliferating cells, normally off Cancer cells: telomerase is active! |
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Organization of DNA in chromosomes
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DNA is coiled around histone proteins (H2A, H2B, H3, H4), resulting in nucleosome, nucleosome is further ordered into chromatin fibers
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Protein DNA interactions
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1. Hydrogen bonding occurs btw amino acid side chains and DNA bases for recognition
2. Most of base contacts with a.a. are in the major groove 3. Proteins have alpha helical regions that can fit into the groove of B-form DNA 4. Multiple DNA binding domains are required for site specific recognition. |
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DNA replication initiation
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Humans apparently have an ORC (though we aren't completely sure).
Have MCM (helicase) that unwinds DNA, RPA (single stranded binding proteins): inhibit reannealing of strands |
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Werner's syndrome and Bloom Syndrome
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Deficiencies in helicase
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DNA elongation
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DNA primase- synthesizes 10 nt primer
DNA polymerases: add nucleotides sequentially to the 3' OH (nucleophillic attack of the 3'OH to 5' phosphate of triphosphate bond) |
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Replication fork
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pol alpha primase-synthesizes RNA primer
pol delta and pol epsilon: catalyze DNA synthesis (also have exonuclease activity!), they are also high fidelity! Replication factor C: required to load DNA polymerase on it PCNA: allows DNA pol to remain on strands |
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Lagging strand
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DNA synthesis always occurs 5' to 3', but 3'-5' synthesis needs to occur on the other strand. How do we fix this? Okazaki fragments
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Sealing of nicks
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To join the fragments, a DNA ligase is required post excision of RNA fragments.
DNA ligase adds a phosphate to the 5' phosphate so that 3'OH can attack that phosphate and one AMP gets left |
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Nucleotide analogues
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Aciclovir, AZT, all work by virtue of inhibiting the reverse transcriptase from incorporating nucleotides has no 3'OH to perform a nucleophilic attack!
AZT however is damaging to mitochondrial DNA polymerase (gamma) |
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DNA polymerase gamma
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mitochondrial DNA synthesis
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Cell Cycle
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Consists of 4 stages (another stage is called G0: quiescent phase)
G1: contains a restriction point (R1), increases cell size, nutrients, and growth factors G1-cyclin with Cdk has a checkpoint at R1. |
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Kinases
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Enzymes that add phosphates
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Cdk
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Complex of a cyclin and a kinase
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Tumor supressors
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p53: allows for cell growth arrest, cell apoptosis post damage,
mutant or no p53: no cell growth arrest, inefficient DNA repair, malignant potential |
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p53
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functions at G1-S chekpoint, checks for DNA damage
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Li-Fraumeni syndrome
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associated with individuals with mutant p53, risk of developing tumors at multiple sites
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DNA repair
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Mismatch repair
Excision repair Removal of uracil |
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Mismatch repair in prokaryotes
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prokaryote: have mut SHL system which recognizes mismatched base pairs by virtue of methylation of adenines. mutS: dGATC site, strand incision, mutH, mutL: protein protein interface, helicase and then exonuclease, and then DNA pol III, SSB, and DNA ligase
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Mismatch repair in humans
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have an analogue of that in prokaryotes, mutations in human factors mutMSH and mutMLH have been implicated in cancers such as HNPCC
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trinucleotide repeats
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mismatch repair pathway may also affect and stabilize long sequences of trinucleotide repeats.
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Huntington's disease
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CAG trinucleotide repeat, inverse correlation between number of CAG repeates and age of onset
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excision repair
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incision, excision, resynthesis, and ligation,
DNA and UV damage, you form thymidine dimers |
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excision repair of UV damage in prokaryotes
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uvrABC system, cleaves the damaged DNA strand, small gap, filled by DNA pol I, 3' end is joined to original DNA by DNA ligase
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xeroderma pigmentosa
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biochemical defects in the repair process
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removal of uracil from DNA
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cytosine spontaneously deaminates to form uracil but a low but significant rate. Uracil DNA glycosidase, recognizes uracil, and removes it, creating an apurinic site. AP endonuclease recognizes AP site and nicks backbone.
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Biochemistry of mutation
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substitutions
deletions insertions |
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Chemical mutagens
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nitrous acid (deamination)
cytosine to uracil adenine to hypoxanthine |
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Alkylation
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N-7 position of guanine, results in loss of guanine residue from the DNA double strand
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polycylic hydrocarbons
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intercalators: proflavin and ethidium bromide
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radiation
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exposure of cells to ionizing radiation causes removal of electrons from molecules
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ames test
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plate bacteria on dish with a certain mutation that is unable to make an amino acid, place bacteria on liver homogenate
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restriction endonucleases
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fragmentation of DNA molecules, caused by bacteria.
DNA bases can be protected by methylation, can generate a wide variety of restriction fragments, can create 5' overhangs (EcoRI), 3' overhangs (HhaII), or blunt ends (Hae III) |
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Gel electrophoresis
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separate fragments based on size, very large fragments are separated by pulsed gel electrophoresis
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Southern Blot analysis
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technique used to identify DNA fragments, cut up DNA with endonucleases, gel electrophoresis, and then blot onto membrane, and hybridize with labeled probe (DNA or RNA, frequently of CDNA)
Do autoradiography |
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Applications of Southern blot analysis
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identifications of gene defects (Deletions and insertions),
Point mutations (B-globin) RFLP's: DNA variations, presence of mutant genes ASO's: take a oligonucleotide probe and see if it binds? If not, probably a mutant |
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Northern Blots
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technique to detect mRNA molecules, RNA is located by hybridization with single stranded DNA or RNA
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Western Blots
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Separate proteins on SDS polyacrylamide gel, then have a radiolabeled antibody that will bind to it
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Polymerase chain reaction
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used to amplify DNA molecules, have to primers, have them anneal at a certain temp after denaturation, and then add heat stable polymerase and dNTP's,
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RT-PCR
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use RT to convert RNA to DNA, and then do PCR
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single strand conformation polymorphism
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PCR products of interest are separated on a gel and separated into single strands by chemical means, mutation is present, conformationally altered
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DNA sequencing
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Sanger dideoxy sequencing: use ddNTP's that are fluorescently labeled, dNTP's, put one ddNTP in each lane, as well as 3 others in the lane, and then do gel electrophoresis. Will come up with a series of bands that can be separated by gel electrophoresis.
To read the strand complement to the template strand in the 5'-3' direction, read from the bottom to the top |
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Methods for Studying protein DNA interactions
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DNA band shifts: simple assay to determine if a protein interacts with a particular DNA fragment (band shifts because of increased molecular weight)
DNAse I footprinting assay: used to determine where the protein is binding, DNA bound to protein is protected from DNAse I |
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gene cloning
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you can insert restriction fragments in bacteria to result in formation of a recombinant plastid
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DNA libraries
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DNA is cleaved into thousands of fragments and then cloned into a vector, genomic libraries
cDNA libraries |
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screening DNA library
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use a probe
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DNA fingerprinting
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Use VNTR's to create bar codes of an individual by electrophoresis of endonucleased fragments
Can also use PCR of di, tri, and tetranucleotide sequences |
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RNA
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differs from RNA by not having a 3' OH, RNA can't form double helix because of steric hindrance by the 2' OH, AU base pair forms as well as with AT
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Transcription
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From DNA to RNA
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Template Strand
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RNA pol uses to read
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Coding strand
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replace the T's with U's and you get your coding sequence
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RNA polymerase
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Ribonucleotides are added to the 3' OH, unlike DNA polymerases, they can initiate chains and don't need a primase!
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RNA Pol I
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synthesis of 18S, 5.8S, and 28S rRNA
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RNA pol II
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transcriptions of genic products
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RNA pol III
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small RNA, tRNA's, and 5s RNA
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RNA pol I catalyzed rRNA synthesis
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primary transcript (45S) undergoes a series of specific cleavages which lead to 18S, 5.8S,, and 28S ribosomal chains,
28 and 5.8 go at the 60S,, 18S goes to the 40 Factors B and S help for transcription |
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RNA pol III
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120nt synthesis of 5S tRNA occurs, activation region lies within the gene, assembly factors TFIIIC enable binding of TFIIIB and transcription begins, some additional processing occurs
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RNA pol II
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promoter: TATA box, TBP (subunit of TFIID) binds to these sequence. TFIIB interacts with TFIID. TFIIB and TFIID are basal transcription factors
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Enhancers
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increase pol II transcription, function at great distances, and can be located upstream, downstream, or within a gene
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Cap structure of mRNA
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7-methylguanylate cap is added to the 5' end of nascent RNA, 5-5 linkage methylation of 2' OH.
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polyA addition
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AAUAA invariant sequence bound by CPSF which binds cleavage factors, poly A polymerase adds 250 A residues, poly A addition is selective, only RNA chains destined to beomce mRNA receive polyA tail
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Splicing
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splicing together of RNA segments involves cleavage of introns out of primary transcript, GU A AG, cleavage infront of GU site (pyrimdine rich sequence in front of 3' splice site as well). Circularization happens by a branch point that connects 5'phosphate of guanine to an 2'OH of an a residue). This forms a lariat! Then the remaining exon is ligated with the other exonic segment.
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sNRP's
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catalyic ribonucleoproteins that allow for splicing of RNA
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Correct splicing of mRNA
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medically relevant! alpha and beta thallasemmias, 25% are caused by mutations in sequences that are required for correct splicing.
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actinomycin D
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general inhibitor of DNA dependent RNA synthesis, intercalates within GC bp, sensitive to synthesis of ribosomal RNA
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alpha amanitin
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inhibits RNA polymerases II and III
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rifampicin
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bacterial RNA polymerase is sensitive to this, inhibits initiation step of RNA synthesis
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cDNA cloning
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1. Use a polyDTTTT column to purify mRNA
2. Use reverse transcriptase 3. Treat with alkali, degrade RNA 4. Hairpin by DNA pol make a complementary strand, 5. Treat with S1 nuclease |
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housekeeping proteins
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proteins that are concerned with basic and metabolic functions common to all cells
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Configuration of genes in chromatin
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DNA of eukaryotic chromosomes is associated with large amounts of protein and compacted into chromatin.
DNAse I experiments show sensitivies to specific stretches of DNA. |
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heterochromatin
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condensed chromatin
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euchromatin
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uncondensed chromatin, genes are active under here.
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Locus control regions
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B globin locus, expression of gene families can be regulated by an element acting over long distances. LCR's appear to regulate chromatin organization
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nucleosome remodeling
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protein complexes SWI SNF can alter chromatin structure, remodel nucleosome structure
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histone acetylation
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acetylation of lysine residues on the protein, leads to unfolding of the chromatin (DNA is negatively charged), two negative charges repel,
can also have deacetylases, which make DNA and histone reassociate |
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DNA methylation
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5-methylcytosine occurs by DNA methyl transferases. Have CG resideus that are methylated. Different tissues have different methylation patterns.
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CpG islands
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housekeeping genes commonly contain CpG islands, long CpG stretches of DNA that almost lack methylation
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basal transcription factors
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essential for initiation of transcription of all genes. Basal factor assembly also depends on activators. Enhancers interact with activators, which activators interact with BTFs through coactivators.
Can also have repressors, that interfere with function of activators etc. |
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issues related to activation of transcription
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protein protein contacts:
modular proteins (dimers, DNA binding, activation of transcription) covalent modification: certain transcription factors have enzymatic activities such as phosphoryaltion and acetylation that modify properties and activities |
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inducible gene expression
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heat shock: HSF changed to an active form on temperature change that binds to specific DNA upstream of certain genes.
Allows for transcription |
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Steroid hormones
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soluble in lipid membranes and then they cna diffuse into the cells. Bind to intracellular steroid receptors that are site specific binding molecules, appear to displace nucleosomes.
Binding sites on DNA for hormone steroid receptor complex are called response elements |
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Cell type specific transcription
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vast range of cell types, have representative transcription factors that mediate gene expression in specific cell types, factors are normally synthesized, or activated in only one tissue, resulting in cell type specific transcription whose genes are dependent on them
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DNA microarrays
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consists of a slide, containing DNA molecules attached at specific spots. DNA is attached by virtue of electrostatic interactions.
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Monitoring geneome wide expression
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DNA is used to monitor upregulation or downregulation of certain genes. mRNA's are isolated from normal and affected patients and is made into cDNA, If CDNA's are complentary, they will hybridize. Fluorescence tags help qualitiatively identify amount of CDNA hybridized, indicating upregulation or downregulation
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Therapies
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Antisense therapy:
Have a specific oligonucleotide delivered |
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RNA interference
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use dsRNA's to deliver to tissue which then get cut up and then recruited by RISC, which deletes specific mRNA's
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ribosomes
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have RNA and protein
60S 40S (eukaryotes) 50S and 30S (prokaryotes) |
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mRNA
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species of RNA that carries information for coding of proteins
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degeneracy
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multiple codons code for one amino acid
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tRNA
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plays major role in expression of genetic information, many different tRNA's, contain interesting bases, have characteristic cloverleaf folding.
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activation of amino acids by linkage to specific tRNA's
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ATP and amino acid get activated to form aminoacyl AMP, this is catalyzed by aminoacyl t-RNA synthetase
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formation of tRNA peptide
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aminoacyl tRNA synthetase takes aminoacyl adenylate and makes the reaction between 3' hydroxyl with the 5' phosphate with the amino acid
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Codon and anticodon interaction
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The loop opoosite the site for amino acid binding is an important portion of the tRNA molecule.
3' base of the codon and the 5' base of the anti-codon are orientated such that relaxed bonding occurs |
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polypeptide chain initiation
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initiator t-RNA starts with methionine as their N-terminal residue
A special met-tRNA functions in the initiation process |
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initiator transfer tRNA
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met-tRNA
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binding of metTRNA to 40S subunits
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metTRNA binds to eIF-2 and GTP. eIF2-GTP-Met-tRNA binds to 40S subunit
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binding of the small ribosome subunit to initiation site on the mRNA
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eIF4F recognizes and associates with the 7-mG cap structure at the ened of the 5' end of eukaryotic mRNA:s.
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formation of 80S complex
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large subuint binds to the small subunit, met-TRNA is bound ito the peptidyl or P site in the 80S complex. Aminoacyl site is available for the attachment
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Polypeptide chain elongation
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amino acid to be added to the growing polypeptide chain binds as an aminoacyl t-RNA binds to the A site. A soluble protein called, EF-1 is required for this binding,, forms a ternary complex with GTP. This binding is followed by GTP hydrolysis and release of EF-1, GDP, and Pi
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Peptide bond formation
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NH2 of aminoacyl tRNA attacks peptidyl t-RNA throuh peptidyl transferase
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translocation
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peptidyl t-RNA must be transferred to the next site, the growing polypeptide chain is in the P site. Translocation process requires a factor called EF-2, GTP hydrolysis powers the translocation process.
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termination of protein synthesis
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UAA, UAG,, UGA, are all codons for termination of protein synthesis, a soluble protein called termination factor, binds to the A site and promotes cleavage.
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polyribosomes
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polyribosomes, mRNA is translated simultaneously by multiple ribosomes
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formylated met-TRNA
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met-tRNA, is formylated, met-t-RNA of eukaryotic cells aren't formylated
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polycistronic
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several genes are often transcribed on a single mRNA chain, several termination sites on the mRNA chain
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pribnow box
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helps differentiate initation sites, eukaryotic mRNA don't have shine dalgarno sequences
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secretory proteins
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compartmentalization of secretory proteins, short amino acids at the N-terminal sequence growing polypeptide chains
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signal peptide
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rich in hydrophobic amino acids, signal peptide formed and recognized by a signal recognition peptide, SRP binds to and prevents further translation,
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stop transfer membrane anchor sequences
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proteins destined to the plasma membrane remain associated wit hthe ER membrane
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regulation of translation
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alternative splciing: 35% produces two or more forms of the same protein, that are necessary at stages of development
control of messenger RNA decay: mRNA decays at a characterstic rate, histone mRNA are normally very unstable (lack poly A) |
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regulation of translation of specific mRNA molecules
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ferritin, translationally regulated, ferritin mRNA consists of a stem loop structure (IRE), IRE-BP, when you have iron, you need to make ferritin
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rate of translation
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you can phosphorylate EiF-2, essesntially making it inactive and not allowing translation to occur
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puromycin
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inhibits both eukaryotic and prokaryotic protein synthesis, resembles the terminal portion of aminoacyl t-RNA, binds to the A site, peptidyl puromycin. Interruption of elongation process
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chloramphenicol
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inhibits peptidyltransferase associated with prokaryotic 50 S ribosomal subunit, also inhibits protein synthesis in mitochondria of eukaryotic cells
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streptomycin
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hihgly basic trisaccharide: interferes bwith binding of formyl methionyl tRNA of 30S subuint, incorrect initiation
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tetracylcine
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binds to the 30S subuint and blocks attachment of aminoacyl tRNA's
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erythromycin
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affects 50S subuint and inhibits translocation
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cycloheximide
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effective against 80S ribosomes
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diptheria toxin
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causes inactivation of EF-2 in mammals, toxin catalyzes tranfer of the ADP ribose portion of NAD+ to elongation factor
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base substitution
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amino acid replacement resulting in different A.A.-missense silent mutation.
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loss of termination
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stop codon mutation can result it in it not stopping anymore
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nonsense mutation
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resulting in a premature stop codon
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frame shift mutation
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nucleotides in mRNA are translated in groups of three,, lead to different genetic interpretation
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Henderson Hasselbach Equation
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pH= pka + log [A-]/[HA]
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isoelectric point
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where the amino acid or peptide is electrically neutral.
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isolectric focusing
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separate proteins based on their respective pI's
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protein purification
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use dialysis
ion exchange columns affinity columns (antibody) |
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protein sequence determination
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edman degradation, use ninhydrin stains to identify aromatic amino acids, can do automated peptide sequencing
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collagen
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triple helix containing conserved sequence Glycine-X-X, where X can be hydroxy proline, or proline. Fairly long and different from the alpha helix
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prolyl hydroxylase
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hydroxylates proline residues
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lysyl oxidase
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cuproenzyme that makes a formaldehyde on lysine chains, these formaldehydes can react to form cross links in collagen
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collagen bio-synthesis
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1. protein synthesis occurs through translocation of ER pores via SRP
2. pro alpha chains form in ER 3. selected lysine and proline residues get hydroxylated 4. Selected hydroxylysine residues get glycosylated 5. Proalpha chains assemble 6. Intrachain and interchain disulfside bonds form at the C terminus 7. Procollagen molecule is secretide 8. N and C terminal peptides are cleaved outside of the cell making it into tropo collagen (by collagen peptidases) |
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scurvy
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happens from a lack of absorbic acid, resulting in improper functioning of prolyl hydroxylase
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Ehler's Danlos Syndrome
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defects of fibrillar collagen molecules (type I II or III) or deficiencies in lysyl hydroxylase or procollagen peptidases. Results in very stretchy skin
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Elastin
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Very elastic, has desmosine cross link with allyllysine residues, lot of cross linking, can stretch very well
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osteogenesis imperfecta
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mutation in type I collagen which results in brittle bones, there are no holes in collagen matrix by which bones can properly form
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heme
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protoporyphyrin molecule containing multiple histidine side chains, iron is held in center of ring coordinated with the four histidines
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oxygenated heme iron oxidation state is...
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+2
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deoxygenated heme state is
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+2
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myoglobin
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present in muscle tissue, alpha helices, have two additional histidine residues that have interactions (proximal (F8) and distal (E7)), distal helps stabilize binding of oxygen
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Why doesn't CO bind to heme in myoglobin well despite heme degradation?
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CO is kept at a 120 angle by the proximal and distal histidines, making it have a weak interaction.
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what happens when oxygen binds to iron in heme
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iron goes within the plane
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fetal hemoglobin
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consists of alpha chain and gamma chain, more strongly associated with oxygen due to decreased affinity for 2,3 BPG
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Bohr effect
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Basically describes the effects that a low pH has, it shifts it to the right (we want to unload more oxygen at actively producing tissues)
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Why do sickle cell aneamics at birth don't have a significant problem?
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Because they still have HbF, which has higher oxygen affinity. However, later on, they have problems when their gamma chains get replaced by beta chains
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hydroxyurea
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helps to make a little hbF for treatment of sickle cellers
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