Download MBBS Biochemistry PPT 18 Nucleic Acid Lecture Notes

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1

Objectives

1. What are nucleotides

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2. Why are bases named so

3. What are syn and anti conformers

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4. What are different tautomers

5. Why mutation is common in genes

6. Biomedical Importance of nucleotides

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7. Synthetic nucleotide

8. Clinical problem and MCQ

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A 36 years old male patient is diagnosed

with Gout. Doctor has decided to

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prescribe Allopurinol.

What modifications in the generic

purine ring would help a pharmacist

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to prepare Allopurinol?

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What are nucleotides

Why are bases named so

Circumstances of discovery

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Guanine:

Isolated from Guano( bird manure)

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Thymine: from thymus

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Purine and pyrimidine. The atoms are

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numbered according to the international

system.

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Tautomerism of the oxo and amino

Functional groups of purines and

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pyrimidines

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Ribonucleosides: Syn and Anti conformers

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Ribonucleosides: Syn conformer

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Ribonucleotides

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Modification of Polynucleotides

Can generate additional structure

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uncommon naturally occurring

pyrimidines and purines.

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Intermediates in the catabolism of

purine

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Caffeine, a trimethylxanthine.

Theobromine:

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3,7 dimethyl xanthine

Theophyline:

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1,3 dimethyl xanthine

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Why UV light causes

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mutagenesis?

Conjugate double bond

How the concentration of nucleic

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acid and nucleotides are

expressed and its implication

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as research tool

Absorbance at 260 nm

Purity of nucleic acid

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Biomedical importance

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1.Serve as precursor of nucleic acid

2.Principal biologic transducer of free energy

e,g AT P, GTP

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3.Second messanger

cAMP, cGMP

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cAMP and cGMP

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4. Methyl group donor and sulfate donor

Adenosine 3' phosphate-5'

phisphosulfonate

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S-Adenosylmethionine

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5. Allosteric regulator:

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e,g ATP acts as allosteric inhibitor of phosphofructokinase

6. Sugar derivatives

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a. UDP glucose and galactose: Biosynthesis of glycogen,

glucosyl disaccharide, oligosaccharides of glycoprotein

and proteoglycan

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b. UDP glucuronic acid : Glucuronide conjugation of

bilirubin, drugs

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7. Lipid derivatives

CDP acyglycerol: participates in biosynthesis of

phosphoglyceride, shingomyelin, sphingosine

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8. Vitamin derivatives: Nucleotides

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form a portion of Coenzymes

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Many coenzymes and related

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compounds are derivatives of

Adenosine monophosphate

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Example of coenzymes : Derivative of

ribonucleoside

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Clinical Application:

1. Chemotherapy of cancer and AIDS

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2. As suppressor of immune response

During Organ transplantation

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Synthetice Nucleotides and

their clinical implications

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Synthetic purine analogs

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Synthetic pyrimidine analogs

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chemotherapy of cancer

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organ transplantation to

suppress immunologic

rejection

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Synthetic derivatives of nucleoside

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triphosphates

Incapable of release of

Terminal phosphoryl group

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Used as research

tool

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What is DNA and RNA?

Polynucleotide

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How to represent The primary structure

of a polynucleotide

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Summary
1. Under physiologic conditions, the amino and

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oxo tautomers predominate

2. Nucleic acids contain traces of 5-methylcytosine,

5-hydroxymethylcytosine, pseudouridine (),

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and N-methylated heterocycles.

3. D-ribose or 2-deoxy-D-ribose linked to N-1 of a

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pyrimidine or to N-9 of a purine by a -glycosidic bond

anti conformers predominate

4. A primed numeral indicates the hydroxyl to which the

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phosphoryl group of the sugars of mononucleotides

(eg, 3-GMP,5-dCMP) is attached

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5. Additional phosphoryl groups linked to the first

by acid anhydride bonds form nucleoside

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diphosphates and triphosphates.

6. Nucleoside triphosphates have high group transfer

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potential and participate in covalent bond syntheses

7. The cyclic phosphodiesters cAMP and cGMP function

as intracellular second messengers.

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8. Mononucleotides linked by 3 5-phosphodiester

bonds

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9. When represented as pTpGpT or TGCATCA, the

5-end is at the left, and all phosphodiester bonds

are 3 5.

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Clinical Problems and

Multiple choice questions

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1. Which of the following statements about

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,-methylene and ,-imino derivatives of purine

and pyrimidine triphosphates Is CORRECT?

a. They are potential anticancer drugs

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b. They are precursors of B vitamins.

C. They readily undergo hydrolytic removal of

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the terminal phosphate.

d. They can be used to implicate involvement of

Nucleotide triphosphates by effects other than

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phosphoryl transfer

Ans d

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2. Which of the following statements about nucleotide

structures is NOT CORRECT?

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a. Nucleotides are polyfunctional acids.

b. Caffeine and theobromine differ structurally solely with

respect to the number of methyl groups attached to their

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ring nitrogens.

c. The atoms of the purine ring portion of pyrimidines are

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numbered in the same direction as those of a pyrimidine.

d. NAD+, FMN, "active methionine" and coenzyme A all

Are derivatives of ribonucleosides

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e. 3,5-Cyclic AMP and GMP (cAMP and cGMP) serve as

second messengers in human biochemistry.

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Ans c.

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A 36 years old male patient is diagnosed

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with Gout. Doctor has decided to

prescribe Allopurinol.

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What modifications in the generic

purine ring would help a pharmacist

to prepare Allopurinol

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Ans: Exchange of C and N at 7 and 8 positions

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VIDEO for DNA structure

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Nucliec acid stucture and Function

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Objectives

1. Functions of nucleic acid

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2. What are the different forms of DNA

3. What are complementary pairs and why

4. Why there are specific number of hydrogen

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bonds

5. Why DNA is more stable-

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6. Chargaffs rule

7. Watson Crick model

8. Tm

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Nucleoprotein

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Functions of nucleic acid

The main functions is to store and transfer genetic information.

The deoxyribonucleic acid is the storage place for

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genetic information in the cell.

The function of the nitrogenous base sequences in the

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DNA backbone determines the proteins being synthesized

DNA controls the synthesis of RNA in the cell.

The genetic information is transmitted from DNA

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to the protein synthesizers in the cell.

The function of the double helix of the DNA is that

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no disorders occur in the genetic information if it is lost or damaged.

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Functions of nucleic acid contd

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RNA directs the production of new protein by

transmitting genetic information to the protein

building structures

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m-RNA takes genetic message from RNA.

t-RNA transfers activated amino acid, to the site of

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protein synthesis.

r-RNA are mostly present in the ribosomes, and

responsible for stability of m-RNA.

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base pairing between complementary

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deoxynucleotides: formation of hydrogen bonds

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Why RNA is more susceptible to

degradation

Hydrolysis of RNA under alkaline

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conditions

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Hydrolysis of RNA

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Based on data collected from DNAs of a great many different species,

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Chargaff concluded:

1. The base composition of DNA generally varies

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from one species to another.

2. DNA specimens isolated from different tissues of

the same species have the same base composition.

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3. The base composition of DNA in a given species

does not change with an organism's age, nutritional

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state, or changing environment.

4. In all cellular DNAs, regardless of the species,

the number of adenosine residues is equal to the

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number of thymidine residues (that is, A T),and

the number of guanosine residues is equal to the

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number of cytidine residues (G C).

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The sum of the purine

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residues equals the sum of

the pyrimidine

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residues; that is, A+G=T+C

These quantitative

relationships, sometimes

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called "Chargaff's rules,"

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The Watson and Crick

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model of the double-

helical structure of the B

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form of DNA

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Copyright to Harper

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Structures of different forms of DNA

Different forms: A-E &Z

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A form: DNA-RNA hybrids and

RNA-RNA double stranded regions

Z form: alternating purines and pyrimidi

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Copyright to lippincott

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Melting temperature of DNA molecules

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with different nucleotide composition

Adopted from lippincott

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For sequences less than 14 nucleotides the formula is:

Tm= (wA+xT) * 2 + (yG+zC) * 4

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where w,x,y,z are the number of the bases A,T,G,C in the

sequence, respectively.

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For sequences longer than 13 nucleotides, the equation used is

Tm= 64.9 +41*(yG+zC-16.4)/(wA+xT+yG+zC)

Both equations assume that the annealing occurs under

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the standard conditions of 50 nM primer, 50 mM Na+, and pH 7.0.

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Base composition

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Salt concentration:

10 fold monovalent cation concentration

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increase=Tm?

Organic solvent:

Fomamide addition= Tm ?

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Factors influencing Tm

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Importance of melting temperature
Video on PCR

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Annealing temperature

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RNA

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Copyright to Harper
Secondary structure of RNA

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Copyright to Harper

Cap structure attached to

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eukaryotic mRNA

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Copyright to Harper
Components of mammalian

ribosome

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Copyright to Harper

A subset of small RNA (20-1000

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nucleotides)

Involved in rRNA and mRNA processing

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and gene regulation

U1,U2,U4,U5,U6---involved in intron

removal

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U7 ---in production of correct 3' end of

histone mRNA

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Small Nuclear RNA (snRNA)

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tRNA secondary

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structure

Copyright to lippincott

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Tertiary structure of tRNA

Copyright to lippincott

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DNA consists of four bases--A, G, C, and T--that are held in linear

array by phosphodiester bonds through the 3 and 5 positions of

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adjacent deoxyribose moieties.

DNA is organized into two strands by the pairing of bases A to T

and G to C on complementary strands. These strands form

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adouble helix around a central axis.

The 3 ? 109 bp of DNA in humans are organized into the haploid

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complement of 23 chromosomes. The exact sequence of these 3

billion nucleotides defines the uniqueness of each individual

RNA exists in several different single-stranded structures, most of

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which are directly or indirectly involved in protein synthesis or its

regulation. The linear array of nucleotides in RNA consists of A, G,

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C, and U, and the sugar moiety is ribose.

The major forms of RNA include mRNA, rRNA, tRNA, and snRNAs

and regulatory ncRNAs.

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Certain RNA molecules act as catalysts (ribozymes)--e.g,.the

large rRNA component performs the peptidyl transferase activity.

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Summary

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While studying the structure of a small gene that was

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recently sequenced during the Human

GenomeProject, an investigator notices that one

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strand of the DNA molecule contains 20 As, 25 Gs, 30

Cs, and 22 Ts . How many of each base is found in the

complete double-stranded molecule?

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A. A = 40, G = 50, C = 60, T = 44.

B. A = 45, G = 45, C = 52, T = 52.

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C. A = 50, G = 47, C = 50, T = 47.

D. A = 42, G = 55, C = 55, T = 42

E. A = 44, G = 60, C = 50, T = 40.

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MCQ1

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Any proteins that are structurally associated

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with nucleic acids, either DNA or RNA

Nucleoproteins tend to be positively charged,

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facilitating interaction with the negatively

charged nucleic acid chains.

A deoxyribonucleoprotein (DNP) is a

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complex of DNA and protein.

examples are nucleosomes-DNA is wrapped around

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clusters of eight histone proteins to form chromatin

Function : regulating DNA replication and

transcription.

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involved in homologous recombination, a process

for repairing DNA

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Nucleoprotein

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Ribonucleoproteins: a complex

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of ribonucleic acid and RNA-

binding protein

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Examples: ribosome, the

enzyme telomerase, RNase P, hnRNP and

small nuclear RNPs

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Functions: DNA replication, regulating

gene expression and regulating the

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metabolism of RNA

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structure of

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nucleosomes.

Copyright to lippincott

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Structural organization of euk

Copyri a

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ght ry

to lippinc o

ott tic DNA

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Compaction of DNA

in a eukaryotic chromosome

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Copyright to Lehninger

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Copyright to Lehninger
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Video on DNA Packaging

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Euchromatin: Transcriptional y

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active chromatin, stains less

densely

Heterochromatin:

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Transcriptional y inactive

chromatin, densely packed

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during interphase

Euchromatin and Heterochromatin

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Constitutive : Found near

centromere and telomere

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Facultative : One X chromosome

in mammalian female

Hetero Chromatin:

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Roles of modified histones

Modification

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Effect

Acetylation of histones H3

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gene transcription

and H4

Acetylation of core histones

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Chromosomal assembly during

DNA replication.

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Phosphorylation of histone H1 condensation of chromosomes

during the replication cycle

ADP-ribosylation of histones

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DNA repair

Methylation of histones

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activation and repression of gene

transcription.

Monoubiquitylation

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gene activation, repression, and

heterochromatic gene silencing

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Sumoylation of histones

transcription repression

(SUMO; small ubiquitin-related

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modifier)

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The relationship between chromosomal DNA and mRNA

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Sequence classes of genome

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Unique sequence DNA: single copy gene that code for protein

>50%

Repetitive sequence DNA: include sequences that vary in

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copy number from 2 to 10^7

30%

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Highly repetetive: 5-500 base pairs length repeated

1-10 million copies per haploid
Clustered

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Transcriptionally inactive
Structural role

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Moderately repetitive DNA sequences

< 1 million copies per haploid genome

Long/sh Interspersed repeats

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Transcribed by RNA poymerase II

LINES (Long interspersed repeat sequences)

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20,000-50,000 copies of 6-7 kbp

SINES (Short interspersed repeat sequences)

70-300 bp > 100,000 copies per genome

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e,g Alu family

Both types appear to be Retroposons:

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Disastrous consequence of transposition : Neurofibromatos7i8s
Microsatellite repeat sequences

2-6 bp sequences repeated upto 50 times

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Most common dinucleotide repeats

AC repeat sequences occur at 50,000-100,000 locations

Useful in constructing genetic map

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Useful to screen large number of family members rapidly

Trinucleotide repeat sequences

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CGG---Fragile X syndrome

CAG---Huntington' Chorea

CTG--myotonic dystrophy

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CAG--Spinobulbar muscular atrophy

Kennedy disease

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Major Features of Human Mitochondrial

DNA

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? Is circular, double-stranded,

? Contains 16,569 bp

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? Encodes 13 protein subunits of the respiratory chain

Seven subunits of NADH dehydrogenase (complex I)

Cytochrome b of complex III

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Three subunits of cytochrome oxidase (complex IV)

Two subunits of ATP synthase

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? Encodes large (16S) and small (12S) mt ribosomal RNAs

? Encodes 22 mt tRNA molecules

? Genetic code differs slightly from the standard code

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UGA (standard stop codon) is read as Trp

AGA and AGG (standard codons for Arg) are read as

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stop codons

? Contains very few untranslated sequences

? High mutation rate (5-10 times that of nuclear DNA)

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? Comparisons of mtDNA sequences provide evidence about

evolutionary origins of primates and other species

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Transposon

Common in all types of organisms are short pieces of

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DNA (usually less than 10Kb in length) that

can move from one position to another

in the chromosome of a cell.

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Retroposon:

Eukaryotic genomes contain a special type of

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Transposable elements, called retroposons,

which use reverse transcriptase

to transpose through an RNA intermediate.

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DNA in eukaryotic cells is associated with a

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variety of proteins, resulting in a structure called

chromatin.

Much of the DNA is associated with histone

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proteins to form a structure called the

nucleosome. Nucleosomes are composed of an

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octamer of histones around which about 150 bp

of DNA is wrapped.

Histones are subject to an extensive array of

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dynamic covalent modifications that have

important regulatory consequences.

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Nucleosomes and higher-order structures

formed from them serve to compact the DNA.

Summary

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DNA in transcriptionally active regions is

relatively more sensitive to nuclease attack in

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vitro; some regions, so-called hypersensitive

sites are exceptionally sensitive and are often

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found to contain transcription control sites.

Highly transcriptionally active DNA (genes) is

often clustered in regions of each chromosome.

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Within these regions, genes may be separated by

inactive DNA in nucleosomal structures.

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After transcription, during RNA processing,

introns are removed and the exons are ligated

together to form the mature mRNA that appears

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in the cytoplasm; this process is termed RNA

Sus pm

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licinm

g.ary

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Epigenetics

Information that is passed from one genetation to

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the next ? to daughter cells at cell divisions or from

parent to offspring ?but is not encoded on

DNA sequences is referred to as epigenetic

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information.

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1. DNA Methylation

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A covalent modification of nucleotide cytosine

at 5' position

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By the enzyme DNA methytransferase 1

DNA methylation is the most useful epigenetic

marker for human diseases studies because it is

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stable over a period of decades and is present in

archival specimen including paraffin blcks

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Epigenetic information takes 3

forms

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2. Post translational modifications of

nucleosomal histones

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ATP independent process involving acetylation,

phosphorylation, ubiquitylation

Post translational modifications act through

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recruitment of transcription factor, activation of

transcriptional enhancers, recruitment of

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repressive proteins and interaction with DNA

methylation machinery

Second form of epigenetic

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information

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Higher order Chromatin structure

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Example of which include loop organization

revealed by chromosome conformation capture

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method

Large organized chromatin lysin modifications

Nuclear lamina associated domain

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Third form of Epigenetic

information

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Diet

Deprivation of methionine and folate lead to

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liver and colon cancer

Folate deficieny--- impaired biosynthesis of active

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precursor for DNA methylation, S adenosyl

methionine---Impairs synthesis of thymidylate

Exposure to nicotine causes substantial epigenetic

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changes in smokers

Modulation of Epigenetic

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information

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Cancer

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DNA methyltransferases, TET demethylase,

MBD ( methyl CpG binding domain) family of

methylation recognition gene are mutated in

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lymphoma and colon cancer

Variability in DNA methylation was markedly

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increased in the samples from women in whom

cancer developed years later

Aging

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Genome wide hypomethylation in blood is

associated with breast cancer years later

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89

The interconnecting bonds that connecting

the nucleotides of

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RNA and DNA are termed:

A. N-glycosidic bonds

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B. 3-5-phosphodiester linkages

C. Phosphomonoesters

D. -2-phosphodiester linkages

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E. Peptide nucleic acid bonds

MCQ1

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90
Which of the forces or interactions listed

below play the predominant role in driving

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RNA secondary and tertiary structure

formation?

A. Hydrophilic repulsion

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B. Formation of complementary base pair

regions

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C. Hydrophobic interaction

D. van der Waals interactions

E. Salt bridge formation

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MCQ2

91

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Which entry below correctly describes the

approximate number of bp of DNA______,

which is separated into _____chromosomes

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in atypical diploid human cell in a

nonreplicating state?

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A. 64 billion, 23

B. 6.4 trillion, 46

C. 23 billion, 64

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D. 64 billion, 46

E. 6.4 billion, 46

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MCQ3

92
All but one of the following histones are

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found located within the superhelix formed

between DNA and the histone octamer; this

histone is

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A. Histone H2B

B. Histone H3

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C. Histone H1

D. Histone H3

E. Hisone H4

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MCQ4

93

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Chromatin can be broadly defined as active

and repressed; a subclass of chromatin that

is specifically inactivated at certain times

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within an organism's life and/or in particular

sets of differentiated cells is termed

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A. Constitutive euchromatin

B. Facultative heterochromatin

C. Euchromatin

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D. Constitutive heterochromatin

MCQ5

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94