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Genes of cancer Cancer is a disease of abnormal cells

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Presentation on theme: "Genes of cancer Cancer is a disease of abnormal cells"— Presentation transcript:

1 Genes of cancer Cancer is a disease of abnormal cells
Cancer cells proliferate in an uncontrolled fashion The causes of cancer are quite diverse but the central role is played by DNA mutations in development of cancer

2 Mutation Cancer Chemicals spontaneous Oncogenes radiation
Tumour suppressor genes infection Errors in DNA replication

3 Cancer related mutations affect the same two classes of genes : Oncogenes and tumour suppressor genes Oncogenes are defined as genes whose presence can lead to cancer. They arise by mutation from normal genes (proto oncogenes) that code for proteins involved in stimulating cell proliferation and survival. By producing abnormal forms or excessive quantities of these proteins, oncogenes contribute to the uncontrolled proliferation and survival of cancer cells. In contrast to oncogenes which are abnormal genes, tumour suppressor genes are normal genes whose deletion or loss function can likewise lead to cancer. Tumour suppressor gene produce proteins that either directly or indirectly exert a restraining influence on cell proliferation and survival. The loss of such proteins can therefore allow cell proliferation and survival to evade normal restraints and controls.

4 Genetic flow of information
Chromosomes within our cells have roughly 30,000genes. Each gene codes for a RNA molecule that is either directly used or used as a guide for the formation of protein DNA (store) to RNA (working form ) to protein (product)

5 THE FLOW OF GENETIC INFORMATION
DNA RNA PROTEIN 1 2 3 DNA 1. REPLICATION (DNA SYNTHESIS) 2. TRANSCRIPTION (RNA SYNTHESIS) 3. TRANSLATION (PROTEIN SYNTHESIS)

6 RNA polynucleotide chain
2’ -OH makes 3’, 5’ phosphodiester bond unstable DNA polynucleotide chain

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9 Transcription The process in which a particular section of DNA (genes) are used to produce RNA is known as transcription Goal of transcription is to make an RNA copy of a gene. Only a small percentage of genes are actually being used to make RNA at a particular time in a particular cell

10 The transcription process is tightly regulated in normal cells.
Genes must be transcribed at the correct time. The RNA produced from the gene must be made in correct amount Only the required gene must be transcribed. Turning transcription off is just as important as turning it on.

11 The steps of transcription
A transcription factor recognises the start site (promoter) of a gene to be transcribed The enzyme that makes RNA (RNA polymerase) binds to transcription factor and recognises the start region The enzyme proceeds down the DNA making a copy until the end is reached. The enzyme falls of and RNA is released. This copying process may be repeated numerous times If the RNA is one that codes for protein it will leave the nucleus to enter the cytosol

12 Transcription and promoter elements for RNA polymerase II
+1 transcription element transcription unit TE P exon exon promoter Promoter (DNA sequence upstream of a gene) determines start site (+1) for transcription initiation located immediately upstream of the start site allows basal (low level) transcription Transcription element (DNA sequence that regulates the gene) determines frequency or efficiency of transcription located upstream, downstream, or within genes can be very close to or thousands of base pairs from a gene includes enhancers (increase transcription rate) silencers (decrease transcription rate) response elements (target sequences for signaling molecules) genes can have numerous transcription elements

13 Proteins regulating eukaryotic mRNA synthesis
General transcription factors TFIID (a multisubunit protein) binds to the TATA box to begin the assembly of the transcription apparatus the TATA binding protein (TBP) directly binds the TATA box TBP associated factors (TAFs) bind to TBP TFIIA, TFIIB, TFIIE, TFIIF, TFIIH1, TFIIJ assemble with TFIID RNA polymerase II binds the promoter region via the TFII’s Transcription factors binding to other promoter elements and transcription elements interact with proteins at the promoter and further stabilize (or inhibit) formation of a functional preinitiation complex 1TFIIH is also involved in phosphorylation of RNA polymerase II, DNA repair (Cockayne syndrome mutations), and cell cycle regulation

14 CTD Initiation of transcription and promoter clearance F E B TFIID H
TBP J +1 RNA pol II CTD P P P RNA pol II is phosphorylated by TFIIH on the carboxy terminal domain (CTD), releasing it from the preinitiation complex and allowing it to initiate RNA synthesis and move down the gene

15 Transcription (elongation)
/antisense strand

16 Transcription (termination)
RNA polymerase falls off terminator Coding strand 5’TACGCTGCCCAAGCA Template strand 3’ATGCGACGGGTTCGT RNA sequence Animation:

17 Post-transcriptional modifications

18 Transcription factors
The inappropriate activity of transcription factors has been identified in almost all types of known cancers, Some examples of transcription factors that malfunction in human cancers. P53- The protein that the p53 codes for is important because it controls the transcription of genes involved in causing cells to divide. Rb- The protein product of this gene works by blocking other transcription factors thus preventing transcription of key genes required for cell division to progress. The oestrogen receptor (ER) This protein binds oestrogen and the combination acts as transcription factor to turn on genes that enable target cells to divide.

19 What is translation After hnRNA production through the process of transcription, it is processed in the nucleus to produce mRNA which is then released into cytosol. The mRNA is then recognised by the ribosomal subunits and the message is read by the ribosome to produce a protein. The information for the direction of protein synthesis is encoded in nucleotide sequence that makes up mRNA. Groups of three nucleotides (codons) are read by ribosomes and lead to the insertion of a particular amino acid in growing peptide. After the protein is formed it is folded to perform its function in the cell The proper folding, transportation, activity and eventual destruction of protein are all highly regulated processes. The genes that control these processes are often found to be damaged and malfunction in cancer cells.

20 Messenger RNA (mRNA) 5’ AUG UGA AAUAAA (AAAA)n 3’ initiation codon Cap
5’ untranslated region 5’ m7Gppp AUG translated (coding) region UGA termination codon 3’ untranslated region Eukaryotic mRNAs have a 5' cap followed by a 5' untranslated region. Unlike prokaryotic mRNAs, they do not have a Shine-Dalgarno sequence. Eukaryotic mRNAs also have a 3' poly(A) tail. AAUAAA (AAAA)n 3’ poly(A) tail

21 Protein translation: summary
Elongation Initiation Termination

22 Reading frame reading frame is determined by the AUG initiation codon
every subsequent triplet is read as a codon until reaching a stop codon ...AGAGCGGA.AUG.GCA.GAG.UGG.CUA.AGC.AUG.UCG.UGA.UCGAAUAAA... MET.ALA.GLU.TRP.LEU.SER.MET.SER a frameshift mutation ...AGAGCGGA.AUG.GCA.GA .UGG.CUA.AGC.AUG.UCG.UGA.UCGAAUAAA... the new reading frame results in the wrong amino acid sequence and the formation of a truncated protein ...AGAGCGGA.AUG.GCA.GAU.GGC.UAA.GCAUGUCGUGAUCGAAUAAA... MET.ALA.ASP.GLY The so-called "reading frame" of an mRNA is established by the AUG initiation codon - every subsequent triplet is then read as a separate codon until an in-frame termination codon is reached. The sequence starting with the AUG initiation codon and ending with the in-frame termination codon is called an "open reading frame." Mutations within open reading frames that delete or add nucleotides can disrupt the reading frame. This occurs if the number of nucleotides is not a multiple of three (i.e., 1,2,4,5,7,8,10, etc.). The example above shows that the deletion of one nucleotide changes the reading frame such that every amino acid downstream of the deletion is altered. In addition, because the reading frame is changed, a termination codon (which was not in the original reading frame) is encountered, causing truncation of the protein. What would be the consequence of a three base pair deletion in an open reading frame? Up to 30% of mutations causing human disease are due to premature termination of translation, whether the result of a nonsense mutation or a frameshift mutation. The majority of nonsense alleles give rise to transcripts that are detected and degraded by the nonsense-mediated mRNA decay (NMD) pathway, most likely causing haploinsufficiency (Mendell and Dietz, Cell 107:411; 2001).

23 Cell division and mitosis
For mitosis to take place the following must occur; The genetic material , the DNA in chromosomes , must be faithfully copied. This occurs via a process known as replication The organelle, such as mitochondria , must be distributed so that each daughter cell receives adequate amount to function The cytoplasm of the cell must be physically separated into two different cells. Many features of cancer cells are due to defects in the genes that control cell division.

24 S G0 G1 G2 M The mammalian cell cycle DNA synthesis and
histone synthesis Rapid growth and preparation for DNA synthesis S phase G0 G1 phase Quiescent cells G2 phase M Growth and preparation for cell division phase Mitosis

25 Overview of the major events in mitosis
Interphase prophase metaphase anaphase telophase In case of DNA damage or failure of critical processes P53 stimulates induction of inhibitory proteins that halt DNA replication Defects in p53 are associated with a variety of cancers DNA damage repair or initiation of programmed cell death (apoptosis)

26 Chromosomes and genes

27 DNA synthesis Occurs in the S-phase
Every chromosome is copied with high fidelity. In this process double stranded DNA is unwound and each individual strand is used as a template for the production of complimentary strand. Errors may occur during replication that lead to changes in the nucleotide sequence of the chromosomes. If these changes occur within genes they can alter function of the cell. Human cells have evolved several mechanism to correct errors of this type but they are not perfect. These mistakes can lead to mutated genes. Accumulation of mutations can lead to the development of cancer There are several cancers types that are associated specifically with breakdown of repair processes.

28 DNA replication is semi-conservative
Parental DNA strands Each of the parental strands serves as a template for a daughter strand Daughter DNA strands Daughter strand Parent strand 1 5’GATCCTAGGTACTGACCTTGC3’ Parent strand 2 3’CTAGGATCCATGACTGGAACG5’ Daughter strand

29 Features of DNA Replication
DNA replication is semiconservative Each strand of template DNA is being copied. DNA replication is bidirectional Bidirectional replication involves two replication forks, which move in opposite directions DNA replication is semidiscontinuous The leading strand copies continuously The lagging strand copies in segments (Okazaki fragments) which must be joined

30 Mechanisms of Repair Mutations that occur during DNA replication are repaired when possible by proofreading by the DNA polymerases Mutations that are not repaired by proofreading are repaired by mismatched (post-replication) repair followed by excision repair Mutations that occur spontaneously and in response to mutagens at any time are repaired by excision repaired (base excision or nucleotide excision)

31 Mismatched (post-replication) repair
the parental DNA strands are methylated on certain adenine bases CH3 CH3 mutations on the newly replicated strand are identified by scanning for mismatches prior to methylation of the newly replicated DNA 5’ 3’ CH3 the mutations are repaired by excision repair mechanisms after repair, the newly replicated strand is methylated CH3

32 Some common type of DNA damage
Depurination involves loss of the base adenine or guanine caused by hydrolysis of the bond linking it to DNA chain Deamination involves the removal of an amino group by hydrolysis Pyrmidine dimers are created by an environmental mutagen, the UV radiation in sunlight

33 Deamination of cytosine can be repaired
Deamination of 5-methylcytosine cannot be repaired More than 30% of all single base changes that have been detected as a cause of genetic disease have occurred at 5’-mCG-3’ sites

34 Excision repair (base or nucleotide)
ATGCUGCATTGA TACGGCGTAACT ATGC GCATTGA AT GCATTGA deamination ATGCCGCATTGA uracil DNA glycosylase repair nucleases DNA polymerase b DNA ligase thymine dimer ATGCUGCATTGATAG TACGGCGTAACTATC excinuclease AT AG TACGGCGTAACTATC (~30 nucleotides) DNA polymerase b ATGCCGCATTGATAG TACGGCGTAACTATC DNA ligase ATGCCGCATTGATAG TACGGCGTAACTATC Base excision repair Nucleotide excision repair

35 Defects in DNA repair or replication Xeroderma pigmentosum
Ataxia telangiectasia Fanconi anemia Bloom syndrome Cockayne syndrome 100 human elephant cow Life span 10 Correlation between DNA repair activity in fibroblast cells from various mammalian species and the life span of the organism hamster rat mouse shrew 1 DNA repair activity

36 The control of cell division.
Is the DNA fully replicated? Is the DNA damaged? Are there enough nutrients to support cell growth If these checks fail normal cells will stop dividing Cancer cells do not obey these rules and will continue to grow and divide.

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38 The control of cell division
Cells divide in response to external signals What are the signals that make cells stop dividing A lack of positive external signals Contact inhibition Cellular Senescence

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41 Cell division in cancer cells
Cancer cells can divide without appropriate external signals Cancer cells do not exhibit contact inhibition Cancer cells divide without receiving the ‘all clear’ signal.


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