CARCINOGENESIS AND ITS AFFECT IN DNA…

1. CARCINOGENESIS AND ITS AFFECT IN DNA… PRESENTED BY:- Anamika Das M.Sc Biotechnology 2nd semester Roll no:-06 Gauhati University

2. CARCINOGENESIS • It refers to the process by which a normal cell is transformed into a malignant cell and repeatedly divides to become a cancer. A chemical which can initiate this process is called a chemical carcinogen. Some chemicals which are non-carcinogenic or only weakly carcinogenic can greatly enhance the effectiveness of carcinogenic chemicals. Such "helpers" are called cocarcinogens. They may act by altering uptake or metabolism of carcinogens by cells.

3. Tumors develop in those tissue in which cellular homeostasis has been distributed by Hyperplasia,dysplasia or regenerative changes. • It has been proved that during the division process the cell is more susceptible to carcinogenic factor then at the rest.

5. CARCINOGEN • A carcinogen is an agent directly involved in causing cancer.This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. e.g- inhaled asbestos,certain dioxins and tobacco smoke. • Cancer is a disease in which damaged cells do not undergo programmed cell death.Carcinogen may increase the risk by altering the cellular metabolism which leads to programmed cell death. • Once programmed cell death pathway is damaged,then the cell cannot prevent itself from becoming a cancer cell.

6. CARCINOGENIC FACTOR • Carcinogenic factor can be grouped into • Primary determining factor: chemical substances, carcinogenic action of physical agents & the action of carcinogenic transformation of viruses. • Secondary determining factor: Hereditary determinism • Favoring factor: geographical factor,nutritionfactor,sex, age etc.

7. DNA DAMAGE AND CANCER • In dividing cells,DNA damages ,if not repaired,cause errors during DNA synthesis leading to mutation that can give rise to cancer. • Thus individuals with an inherited impairment in DNA repair capability are often at increased risk of cancer. • Because human somatic cells are diploid,mutant genes are most often recessive when they arise in somatic cell & they usually do not express because of the presence of the wild type copy of the homologous chromosome.

8. There are two chief sources of DNA damages • DNA –adduct forming molecules. • Reactive oxygen and nitrogen species(ROS/RNS)

9. Dna adduct formation • Cancer of the lung and bronchus, which accounts for 29% of the approximately 560,000 yearly cancer deaths in U.S is due to large part of chemical carcinogens in smoke. e.g-benzpyrene-7 ,8-diol -9 ,10-epoxide(BPDE) • Treatment of lung cells with this carcinogen produces a charecteristic pattern of adduct formation at specific sites in p53 gene. • The adduct forming carcinogens in tobacco smoke are also likely important contributes to death from other types of cancer,like cancers of urinary bladder,oral cavity, pancreas ,kidney etc.

10. Benzpyrene Cytochrome p-450(a liver enzyme) Benzpyrene-7, 8-epoxide Epoxidehydrolase Benzpyrene-7, 8 diol Cytochrome p-450 Benzpyrene-7,8-diol-9,10 epoxide Causes liver cancer Fig: conversion of benzpyrenes into carcinogenic derivatives by liver enzymes.

11. The DNA adduct forming compound aflatoxin B1 appear to be major cause of liver cancer in devloping countries. • Aflatoxin B1 forms DNA adducts with guanine in human hepatocytes and is thought to cause G:C to T:A transversion mutation in hepatocellular carcinogenesis.

13. Reactions of dna with ros & rns • A high fat diet leads to increased bile acid secreation,since bile acids emulsify dietary fat for absorption by the small intestine. • Numerous studies have shown that fecal bile acids concentrations are higher in population with high incidence of colon cancer. • The secondary bile acid,deoxycholic acid produced in the liver by bacterial metabolism in the intestine causes both oxidative and nitrosative stress in human colon cells producing both ROS & RNS.

14. Another major source of ROS & RNS leading to cancer is inflammation stemming from chronic infection. • ROS can damage the DNA of the infecting pathogen, DNA of the invaded cells and also nearby host cells that were not invaded. • Infection with HBV & HCV produces inflammation with the release of ROS & RNS.

15. UV DAMAGE & CARCINOGENESIS • Wavelengths of both UVA(320-480nm) & UVB(280-320nm) radiation have been implicated as carcinogens. • UVB radiation is mainly absorbed by epidermal components such as proteins or DNA,wheras UVA radiation penetrates deeply into skin and reaches the lower epidermis and dermal fibroblasts.

16. UVB radiations main effect is DNA damage cause by its direct interaction with the molecule,whlie UVA radiation’s toxicity mainly comes from oxidative damage to skin cell components. • UVB radiation directly damages the genetic information (DNA) within skin cells,causing specific lesions or DNA photoproducts.

17. DNA encodes the genetic information which provides instruction for the structure and function of the living organism. • Cancer cells contain genetic abnormalities in DNA, which affect their growth, replication and ability to survive and invade surrounding tissue.

18. DNA double helix showing sugar-phosphate backbone and the 4 types of nitrogen bases paired together

19. Damage occurs when the chemical bonds within a DNA molecule are altered. • UVB radiation penetrates the cell and is absorbed by the bond between the bases when it then breaks • The un-bonded base then interacts with adjacent bases on the same strand to create new bonds and form dimers,a type of molecular lesion.

20. dna damaged by uvb radiations forms a dimer

21. The effects of UVB on DNA are mostly caused by the formation of these dimers between two adjacent pyrimidines on the same strand. • The two major DNA lesions induced by UVB radiation are CPDs(cyclobutanepyrimidinedimers) and 6-4 pyrimidine photoproducts.

22. The human body has inbuilt system of DNA repair,known as “Nucleotide excision repair” & “Base excision repair” to recognize and eliminate such changes. • Such errors are left unrepaired or incorrectly repaired and the damage becomes permanent,which is called as mutation. • Sometimes the change is benign and the sequence can still be read correctly and the cell functiones properly.

23. Genes involved in skin cancer devlopment. • There are three kinds of genes • Oncogenes • Tumor supressor genes • DNA repair genes • Oncogenes are growth regulators of normal cell division.Oncogenes also give cancer cells to invade new tissue where normal cells would face biological obstacles to crossing these margins.Alternatively they enables the cells to evade apoptosis which will normally occur if they were damaged.

24. Tumor suppressor genes tend to be down regulated and/or inactivated by mutations that may induce cancer transformation. • The DNA mutations resulting from unrepaired pyrimidinedimers frequently arise in the p53 tumor suppressor gene is skin cancer and impede its protective function.The protein produced from the p53 gene in a healthy cell pauses the cell cycle so that DNA damage can be repaired prior to the cell’s replication.

25. Thank you….