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 fashionThe 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 genesinfectionErrors in DNA replication
3 Cancer related mutations affect the same two classes of genes : Oncogenes and tumour suppressor genesOncogenes 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 proteinDNA (store) to RNA (working form ) to protein (product)
5 THE FLOW OF GENETIC INFORMATION DNARNAPROTEIN123DNA1. REPLICATION (DNA SYNTHESIS)2. TRANSCRIPTION (RNA SYNTHESIS)3. TRANSLATION (PROTEIN SYNTHESIS)
9 TranscriptionThe process in which a particular section of DNA (genes) are used to produce RNA is known as transcriptionGoal 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 amountOnly 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 transcribedThe enzyme that makes RNA (RNA polymerase) binds to transcription factor and recognises the start regionThe 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 timesIf 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 +1transcriptionelementtranscription unitTEPexonexonpromoterPromoter (DNA sequence upstream of a gene)determines start site (+1) for transcription initiationlocated immediately upstream of the start siteallows basal (low level) transcriptionTranscription element (DNA sequence that regulates the gene)determines frequency or efficiency of transcriptionlocated upstream, downstream, or within genescan be very close to or thousands of base pairs from a geneincludesenhancers (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 factorsTFIID (a multisubunit protein) binds to the TATA boxto begin the assembly of the transcription apparatusthe TATA binding protein (TBP) directly binds the TATA boxTBP associated factors (TAFs) bind to TBPTFIIA, TFIIB, TFIIE, TFIIF, TFIIH1, TFIIJ assemble with TFIIDRNA polymerase II binds the promoter region via the TFII’sTranscription factors binding to other promoter elements andtranscription elements interact with proteins at the promoterand further stabilize (or inhibit) formation of a functionalpreinitiation complex1TFIIH 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 TBPJ+1RNA pol IICTDPPPRNA pol II is phosphorylated by TFIIH on the carboxy terminaldomain (CTD), releasing it from the preinitiation complex andallowing it to initiate RNA synthesis and move down the gene
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 translationAfter 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 region5’m7GpppAUGtranslated (coding) regionUGAterminationcodon3’ untranslated regionEukaryotic 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)n3’poly(A) tail
21 Protein translation: summary ElongationInitiationTermination
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.SERa frameshift mutation...AGAGCGGA.AUG.GCA.GA .UGG.CUA.AGC.AUG.UCG.UGA.UCGAAUAAA...the new reading frame results in the wrong amino acid sequence andthe formation of a truncated protein...AGAGCGGA.AUG.GCA.GAU.GGC.UAA.GCAUGUCGUGAUCGAAUAAA...MET.ALA.ASP.GLYThe 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 causinghaploinsufficiency (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 replicationThe organelle, such as mitochondria , must be distributed so that each daughter cell receives adequate amount to functionThe 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 synthesisRapid growth andpreparation forDNA synthesisSphaseG0G1phaseQuiescent cellsG2phaseMGrowth andpreparation forcell divisionphaseMitosis
25 Overview of the major events in mitosis Interphase prophase metaphase anaphase telophaseIn case of DNA damage or failure of critical processesP53 stimulates induction of inhibitoryproteins that halt DNA replicationDefects in p53 are associated with avariety of cancersDNA damage repair or initiation of programmed cell death (apoptosis)
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 cancerThere are several cancers types that are associated specifically with breakdown of repair processes.
28 DNA replication is semi-conservative Parental DNA strandsEach of the parental strands serves as atemplate for a daughter strandDaughter DNA strandsDaughter strandParent strand 1 5’GATCCTAGGTACTGACCTTGC3’Parent strand 2 3’CTAGGATCCATGACTGGAACG5’Daughter strand
29 Features of DNA Replication DNA replication is semiconservativeEach strand of template DNA is being copied.DNA replication is bidirectionalBidirectional replication involves two replication forks, which move in opposite directionsDNA replication is semidiscontinuousThe leading strand copies continuouslyThe lagging strand copies in segments (Okazaki fragments) which must be joined
30 Mechanisms of RepairMutations that occur during DNA replication are repaired when possible by proofreading by the DNA polymerasesMutations that are not repaired by proofreading are repairedby mismatched (post-replication) repair followed byexcision repairMutations 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 aremethylated on certainadenine basesCH3CH3mutations on the newlyreplicated strand areidentified by scanningfor mismatches prior tomethylation of the newlyreplicated DNA5’3’CH3the mutations are repairedby excision repair mechanismsafter repair, the newlyreplicated strand is methylatedCH3
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 chainDeamination involves the removal of an amino group by hydrolysisPyrmidine 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 repairedMore than 30% of all single base changes that have been detectedas a cause of genetic disease have occurred at 5’-mCG-3’ sites
35 Defects in DNA repair or replication Xeroderma pigmentosum Ataxia telangiectasiaFanconi anemiaBloom syndromeCockayne syndrome100humanelephantcowLife span10Correlation between DNA repairactivity in fibroblast cells fromvarious mammalian species andthe life span of the organismhamsterratmouseshrew1DNA repair activity
36 The control of cell division. Is the DNA fully replicated?Is the DNA damaged?Are there enough nutrients to support cell growthIf these checks fail normal cells will stop dividingCancer cells do not obey these rules and will continue to grow and divide.
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