Biochemistry assignmentIMPACT OF NUCLEIC

ACIDSSubmitted under the guidance of: Dr. A. K. M. Arif Uddin Ahmed

Submitted by: NIBEDITA AYAN (MBBS student , Xiamen Medical College)

PrefaceThis presentation on Nucleic Acids and their impact has been prepared by Nibedita Ayan under the guidance of Dr. A. K. M. Arif Uddin Ahmed, Lecturer- Department of Pharmacology& Biochemistry, Medical College

of Xiamen University, China

Nucleic acids are very important biopolymers. Nucleic acids were discovered in 1868, when twenty-four-year-old Swiss physician Friedrich Miescher isolated a new compound from the nuclei of white blood cells. The two main classes of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).  DNA is the master blueprint for life and constitutes the genetic material in all free-living organisms and most viruses. RNA is the genetic material of certain viruses, but it is also found in all living cells, where it plays an important role in certain processes such as the making of proteins.

Table of contents What are nucleic acids Discovery of nucleic acids Structure of Nucleic acids Role of nucleic acids Hereditary information carrier

(gene) Protein synthesis Species continuation Central dogma DNA Profiling, Cloning and

Vaccination Aberrations in Nucleic Acids SNP’S NER Bibliography

What are Nucleic acids?? Large Biomolecules; that allow organisms to transfer genetic information

from one generation to the next. These are of two types : DNA and RNA (RNA further subdivided into mRNA, tRNA , rRNA ) Structure:

> all nucleic acids are composed of single monomeric units called nucleotides in their primary structure.

> Nucleotides consist of : pentose sugar- ribose or deoxyribose phosphate groupNitrogenous base- purines(A,G) ,pyrimidines(C,T,U)

Discovery of nucleic acids DNA was first discovered in 1869 by a Swiss biochemist,

Johann Friedrich Miescher. He extracted a gelatinous material that contained organic phosphorus from cells in human pus that was obtained from the bandages of wounded soldiers. He named this material nuclein. 

Ten years later Albrecht Kossel explored the chemistry of nuclein (for which he received the Nobel Prize) and discovered that it contained the organic bases adenine , thymine , guanine and cytosine .

In 1889 Richard Altman removed the proteins from the nuclein in yeast cells and named the deproteinized material nucleic acid. It was not until about 1910 that it was realized that there were two types of nucleic acid, DNA and RNA. 

Structure of Nucleic Acids Nucleic acids are polymers of NUCLEOTIDES Nucleotides are linked by phosphodiester bonds

Nitrogenous bases are of two types : PURINES and PYRIMIDINES

Role of Nucleic acids: Carry genetic information of all hereditary traits Show their effect by specific protein synthesis This feature of nucleic acids is known as the central dogma

of molecular biology Responsible for the continuation of a species Their (helpful) mutations cause evolution Define the phenotype of the organism Other functions of nucleic acids include catalysis (enzyme

like action eg: ribosomes) and co enzyme action (RNA acts as co enzyme for the enzyme telomerase).

Hereditary Information carrier A gene is the molecular unit of heredity of a living organism. The word is used extensively by the scientific community for

stretches of deoxyribonucleic acids(DNA) and ribonucleic acids (RNA) that code for a polypeptide or for an RNA chain that has a function in the organism

DNA :Deoxyribonucleic Acid

DNA is a molecule that encodes the genetic instructions used in the development and functioning of all known living organisms and many viruses .

DNA is well-suited for biological information storage(highly stable molecule).

DNA contains a backbone made up of deoxyribose, phosphate and nitrogenous bases(A,T,G and C)

The two strands of DNA run in opposite directions to each other and are therefore anti-parallel.

Within cells, DNA is organized into long structures called chromosomes. During cell division these chromosomes are duplicated in the process of DNA replication, providing each cell its own complete set of chromosomes.

PROTEIN SYNTHESIS Protein synthesis in biological cells is a complex

procedure involving two processes: TRANSCRIPTION and TRANSLATION

DNA carries the gene coding for the proteins to be produced

Then this information is transcribed to an mRNA. This mRna further passes this information to rRNA and

tRNA which produces the protein, this process is translation.

Types of RNA

Transcription Transcription is the first step of gene expression, in which a particular

segment of DNA is copied into RNA(mRNA, tRNA or rRNA) by the enzyme RNA polymerase.

Transcription proceeds in the following general steps: One or more sigma factor protein binds to the RNA polymerase holoenzyme ,

allowing it to bind to promoter DNA. RNA polymerase creates a transcription bubble, which separates the two strands of

the DNA helix. This is done by breaking the hydrogen bonds between complementary DNA nucleotides.

RNA polymerase adds matching RNA nucleotides to the complementary nucleotides of one DNA strand.

RNA sugar-phosphate backbone forms with assistance from RNA polymerase to form an RNA strand.

Hydrogen bonds of the untwisted RNA-DNA helix break, freeing the newly synthesized RNA strand.

If the cell has a nucleus, the RNA may be further processed. This may include polyadenylation, capping, and splicing.

The RNA may remain in the nucleus or exit to the cytoplasm through the nuclear pore complex.

Translation In translation, messenger RNA (mRNA)—produced

by transcription from DNA—is decoded by a ribosome to produce a specific amino acid chain, or polypeptide

In brief, translation proceeds in four phases: Initiation: The ribosome assembles around the target mRNA. The

first tRNA is attached at the start codon. Elongation: The tRNA transfers an amino acid to the tRNA

corresponding to the next codon. Translocation :The ribosome then moves (translocates) to the next

mRNA codon to continue the process, creating an amino acid chain. Termination: When a stop codon is reached, the ribosome releases

the polypeptide.

Species continuation :DNA replication DNA replication is the process of producing two identical replicas

from one original DNA molecule. This biological process occurs in all living organisms and is the basis

for biological inheritance. DNA is made up of two strands and each strand of the original DNA

molecule serves as a template for the production of the complementary strand, a process referred to as semiconservative replication.

CENTRAL DOGMA:The central dogma of molecular biology is an explanation of the flow of genetic information within a biological system

DNA profiling Forensic DNA profiling (also called DNA testing or DNA typing)

is a technique employed by forensic scientists to identify individuals by characteristics of their DNA. DNA profiles are a small set of DNA variations that are very likely to be different in all unrelated individuals. DNA profiling is used in, for example, parentage testing and criminal investigation.

Although 99.9% of human DNA sequences are the same in every person, enough of the DNA is different that it is possible to distinguish one individual from another, unless they are monozygotic ("identical") twins.

DNA profiling uses repetitive ("repeat") sequences that are highly variable, called variable number tandem repeats (VNTRs), in particular short tandem repeats (STRs). VNTR loci are very similar between closely related humans, but are so variable that unrelated individuals are extremely unlikely to have the same VNTRs.

DNA cloning

DNA Vaccination DNA vaccination is a technique for protecting an organism against

disease by injecting it with genetically engineered DNA to produce an immunological response. Nucleic acid vaccines are still experimental, and have been applied to a number of viral, bacterial and parasitic models of disease, as well as to several tumour models.

Although unproven in the clinical setting, DNA vaccines have a number of potential advantages over conventional vaccines, including the ability to induce a wider range of immune response types.

Aberrations in Nucleic Acids

DNA must be faithfully replicated…but mistakes occur DNA polymerase (DNA pol) inserts the wrong nucleotide base in

1/10,000 bases DNA pol has a proofreading capability and can correct errors

Mismatch repair: ‘wrong’ inserted base can be removed Excision repair: DNA may be damaged by chemicals, radiation, etc.

Mechanism to cut out and replace with correct bases These ‘mistakes’ if permanent are called mutations ;could harmful

or useful for us when inherited by the progeny(which occurs only when mutations take place in germ cells)

When a few mutations accumulate in any group of organisms ,they become reproductively isolated from their precursor which in case of viable and useful mutations could even lead to evolution

MUTATIONS A mutation is a permanent change of the nucleotide sequence of

the genome of an organism, virus, or extrachromosomal DNA or other genetic elements.

Mutations may or may not produce discernible changes in the observable characteristics of an organism. Mutations play a part in both normal and abnormal biological processes including: evolution, cancer, and the development of the immune system, including junctional diversity.

Four classes of mutations are (1) spontaneous mutations (molecular decay) (2) mutations due to error prone replication bypass of naturally occurring

DNA damage (also called error prone translation synthesis) (3) errors introduced during DNA repair, and (4) induced mutations caused by mutagens.

Types of Mutations 

Deletion Genetic material is removed or deleted. A few bases can be deleted (as shown on the left) or it can be complete or partial loss of a chromosome (shown on right).

FrameshiftThe insertion or deletion of a number of bases that is not a multiple of 3. This alters the reading frame of the gene and frequently results in a premature stop codon and protein truncation.

InsertionWhen genetic material is put into another region of DNA. This may be the insertion of 1 or more bases, or it can be part of one chromosome being inserted into another, non-homologous chromosome.

MissenseA change in DNA sequence that changes the codon to a different amino acid. Not all missense mutations are deleterious, some changes can have no effect. Because of the ambiguity of missense mutations, it is often difficult to interpret the consequences of these mutations in causing disease.

Nonsense A change in the genetic code that results in the coding for a stop codon rather than an amino acid. The shortened protein is generally non-function or its function is impeded.

Point A single base change in DNA sequence. A point mutation may be silent, missense, or nonsense.

SilentA change in the genetic sequence that does not change the protein sequence. This can occur because of redundancy in the genetic code where an amino acid may be encoded for by multiple codons.

Splice SiteA change in the genetic sequence that occurs at the boundary of the exons and introns. The consensus sequences at these boundaries signal where to cut out introns and rejoin exons in the mRNA. A change in these sequences can eliminate splicing at that site which would change the reading frame and protein sequence.

Translocation A structural abnormality of chromosomes where genetic material is exchanged between two or more non-homologous chromosomes.

Spontaneous alterations in nucleic acids In a human cell, DNA undergoes spontaneous alterations in structure

(mutations). As a cell ages, the number of mutations increases, making it likely

that a cell’s normal processes may be altered. There is a link between spontaneous mutation, aging, and

carcinogenesis.

Mutations and cancer There are two basic types of genetic mutations: acquired and

germline. Acquired mutations are the most common cause of cancer. These mutations occur from damage to genes during a person’s life,

and they are not passed from parent to child. Tobacco use, exposure to ultraviolet (UV) radiation (such as sunlight

or from tanning beds), viruses, and age can damage genes and cause these mutations. Cancer that occurs because of acquired mutations is called sporadic cancer.

Mutations happen often, and the human body is normally able to correct most of these changes. Depending on where in the gene the change occurs, a mutation may be beneficial, harmful, or make no difference at all. Therefore, the likelihood of one mutation leading to cancer is small. Usually, it takes multiple mutations over a lifetime to cause cancer. This is why cancer occurs more often in older people, for whom there have been more opportunities for mutations to build up.

Types of genes linked to cancer: Many of the genes that contribute to the development of cancer fall into broad categories: Tumor suppressor genes are protective genes. Normally, they suppress (limit) cell

growth by monitoring how quickly cells divide into new cells, repairing mismatched DNA and controlling when a cell dies. When a tumor suppressor gene is mutated (from heredity or environmental factors), cells grow uncontrollably and may eventually form a mass called a tumor. BRCA1, BRCA2, and p53 are examples of tumor suppressor genes. Germ line mutations in BRCA1 or BRCA2 genes increase a woman’s risk of developing hereditary breast or ovarian cancers. The most commonly mutated gene in people who have cancer is p53. In fact, more than 50% of all cancers involve a missing or damaged p53 gene. Most p53 gene mutations are acquired mutations. Germ line p53 mutations are rare.

Oncogenes turn a healthy cell into a cancerous cell. HER2 (a specialized protein that controls cancer growth and spread, found on some cancer cells, such as breast and ovarian cancer cells) and the ras family of genes (genes that make proteins involved in cell communication pathways, cell growth, and cell death) are common oncogenes. Mutations in these genes are almost always acquired (not inherited).

DNA repair genes fix mistakes made when DNA is replicated (copied). If a person has error in a DNA repair gene, these mistakes are not corrected. Mistakes that aren’t fixed become mutations, which may eventually lead to cancer (especially if the mutation occurs in a tumor suppressor gene or oncogene). Mutations in DNA repair genes can be inherited (such as with Lynch syndrome) or acquired. 

Mutations and evolutionGerm-line mutations provide essential genetic variation for evolution, yet pose significant risks for the fitness of a species. The germ-line mutation rate is an order of magnitude lower than somatic cell mutation rates, suggesting that multicellular organisms vary the investments in DNA maintenance to maximize both short-term and long-term benefit. Most deleterious germ-line mutations can be vetted in each generation by natural selection. However, evolution lacks the power to select against those deleterious mutations that produce defects with advanced age. Humans carry a substantial number of genetic differences in their germ-line, differing from each other in roughly 15 million of the 6 billion base-pairs of the genome . Around 12,000 of these single nucleotide polymorphisms affect protein coding sequence . Although most of these are neutral, 700 to 1500 heterozygous polymorphisms are predicted to be deleterious to protein function . In addition to these potentially late-acting deleterious alleles, it has been proposed that some genetic traits may exhibit ‘antagonistic pleiotropy’, or phenotypes that improve survival earlier in life, but become deleterious with increasing age . Induction of cellular senescence or apoptosis in response to DNA damage may function in this manner by preventing cancer in the young, but contributing to reduced tissue homeostasis in the old .

Mutations are essential to evolution.Every genetic feature in every organism was, initially, the result of a mutation. The new genetic variant (allele) spreads via reproduction, and differential reproduction is a defining aspect of evolution. It is easy to understand how a mutation that allows an organism to feed, grow or reproduce more effectively could cause the mutant allele to become more abundant over time. Soon the population may be quite ecologically and/or physiologically different from the original population that lacked the adaptation. Even deleterious mutations can cause evolutionary change, especially in small populations, by removing individuals that might be carrying adaptive alleles at other genes.

The history of the gray treefrog, Hyla versicolor, is an example of mutation and its potential effects. When an ancestral Hyla chrysocelis gray treefrog failed to sort its 24 chromosomes during meiosis, the result was H. versicolor. This treefrog is identical in size, shape and color to H. chrysocelis but has 48 chromosomes and a mating call that is different from the original H. chrysocelis.       

Nucleic acids and Aging correlation It has been proposed that aging results from a defined program that

ensures old individuals are eliminated for the good of the species. Telomeres are sequences at the end of eukaryotic chromosomes that

help stabilize the chromosome. There appears to be a relationship between the length of telomeres at

the end of chromosomes and the age of an individual. The older you are, the shorter your telomeres are.

Germ-line cells (reproductive cells) contain telomerase activity. On-germ-line cells (somatic cells) do not contain telomerase activity. We have a certain length of telomeres that we are born with. As we age, the telomeres get shorter.

SNP’s A Single Nucleotide Polymorphism, or SNP (pronounced "snip")

is a small genetic change, or variation, that can occur within a person's DNA sequence. A single base change found in 1% of an ethnically diverse population is defined as a SNP.

An example of a SNP is the alteration of the DNA segment AAGGTTA to ATGGTTA. Because only about 3 to 5 percent of a person's DNA sequence codes for the production of proteins, most SNPs are found outside of "coding sequences." SNPs found within a coding sequence are of particular interest to researchers as they are more likely to alter the biological function of a protein. Due to recent advances in technology, coupled with the unique ability of these genetic variations to facilitate gene identification, there has been a recent flurry of SNP discovery and detection.

Although many SNPs do not produce physical changes in people, scientists believe that other SNPs may predispose a person to disease and even influence their response to a drug regimen.

Nucleotide excision repair(NER) Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly

because of chemicals (i.e. intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucleotide excision repair (NER), base excision repair (BER), and DNA mismatch repair (MMR). While the BER pathway can recognize specific non-bulky lesions in DNA, it can correct only damaged bases that are removed by specific glycosylases. Similarly, the MMR pathway only targets mismatched Watson-Crick base pairs.

Nucleotide excision repair (NER) is a particularly important excision mechanism that removes DNA damage induced by ultraviolet light (UV). UV DNA damage results in bulky DNA adducts - these adducts are mostly thymine dimers and 6,4-photoproducts. Recognition of the damage leads to removal of a short single-stranded DNA segment that contains the lesion. The undamaged single-stranded DNA remains and DNA polymerase uses it as a template to synthesize a short complementary sequence. Final ligation to complete NER and form a double stranded DNA is carried out by DNA ligase. NER can be divided into two sub pathways: global genomic NER (GG-NER) and transcription coupled NER (TC-NER). The two sub pathways differ in how they recognize DNA damage but they share the same process for lesion incision, repair, and ligation.

The importance of NER is evidenced by the severe human diseases that result from in-born genetic mutations of NER proteins. Xeroderma pigmentosum and Cockayne's syndrome are two examples of NER associated diseases

BIBLIOGRAPHY http://www.britannica.com/EBchecked/topic/421900/nucleic-acid http://www.nature.com/scitable/definition/nucleic-acid-274 http://

www.cancer.org/cancer/cancercauses/geneticsandcancer/genetictesting/genetic-testing-intro

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www.cancer.net/navigating-cancer-care/cancer-basics/genetics/genetics-cancer

http://www.nature.com/scitable/knowledge/library/mutations-are-the-raw-materials-of-evolution-17395346

http://evolution.berkeley.edu/evolibrary/article/mutations_01 http://

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