DNA Replication, Mutation, RepairM 211A MOLECULAR GENETICS 1ST SEMESTER, 2009 NABIL BASHIR DNA Replication, Mutation, Repair a). DNA replication i). Cell cycle/ semi-conservative replication ii). Initiation of DNA replication iii). Discontinuous DNA synthesis iv). Components of the replication apparatus b). Mutation i). Types and rates of mutation ii). Spontaneous mutations in DNA replication iii). Lesions caused by mutagens c). DNA repair i). Types of lesions that require repair ii). Mechanisms of repair Proofreading by DNA polymerase Mismatch repair Excision repair iii). Defects in DNA repair or replication Cell Cycle • The S (for synthesis) phase of the cell cycle is when chromosomes are replicated. This requires DNA synthesis and histone synthesis (the latter to make the proteins that will package the newly replicated DNA). The mammalian cell cycle Rapid growth and preparation for DNA synthesis DNA synthesis and histone synthesis phase S G0 Quiescent cells phase G1 phase M phase G2 Growth and preparation for cell division Mitosis . Hence.Semi-conservative DNA Replication • DNA replication is said to be "semiconservative" because each strand of the DNA double helix serves as a template for the synthesis of a new complementary DNA strand. . the newly replicated chromosome consists of one old and one new DNA strand. DNA replication is semi-conservative Parental DNA strands Each of the parental strands serves as a template for a daughter strand Daughter DNA strands . which are spaced every ~150 kb. the complete length of which needs to be replicated in a relatively short (a few hours) period of time. The resulting "replication bubbles" then fuse together or merge completing the synthesis of the daughter chromosomes. This is accomplished by having multiple origins of DNA replication on each chromsome. . Replication initiates independently at each origin and proceeds bidirectionally as the new DNA strands (red) are synthesized.Origins Of DNA Replication On Mammalian Chromosomes • Each chromosome consists of a very long DNA strand. Origins of DNA replication on mammalian chromosomes origins of DNA replication (every ~150 kb) 5’ 3’ 3’ 5’ bidirectional replication replication bubble fusion of bubbles 5’ 3’ 5’ 3’ daughter chromosomes 3’ 5’ 3’ 5’ . coli chromosome has one origin of replication (ori). This then allows the dnaB and dnaC proteins to bind the single-stranded DNA and further unwind the double helix. As these proteins coalesce. the adjacent DNA is forced to undergo melting into single strands.Initiation Of DNA Synthesis At The E. catalyzed by the dnaB protein which is a DNA "helicase" or DNA unwinding enzyme. . circular E. Coli Origin (Ori) • The single. Initiation of replication begins with the binding of dnaA proteins to the ori sequence. Initiation of DNA synthesis at the E. coli origin (ori) origin DNA sequence 5’ 3’ A A A A A A binding of dnaA proteins 3’ 5’ A A A DNA melting induced by the dnaA proteins dnaB and dnaC proteins bind to the single-stranded DNA dnaA proteins coalesce A A A A A A B C dnaB further unwinds the helix . but can only add onto an existing 3' OH. Hence. DNA polymerases cannot initiate DNA synthesis de novo.• As further unwinding occurs. it is an RNA polymerase. which displaces the dnaA proteins. the dnaG protein binds. In contrast to DNA polymerases. The primer provides a free 3' OH end to initiate DNA synthesis. . the need for the RNA primer. RNA polymerases can initiatate synthesis de novo. This protein is a "primase" and synthesizes a short RNA primer of about 5 nucleotides. As a rule. Because the primase synthesizes an RNA strand. .and synthesizes an RNA primer G RNA primer B C . A A A A A G B C A dnaB further unwinds the helix and displaces dnaA proteins A A A A A A .dnaG (primase) binds.... dnaC. and dnaG proteins. .Primasome • The "primasome" consists of the dnaB. G B C Primasome dna B (helicase) dna C dna G (primase) 5’ template strand 3’ OH 5’ RNA primer (~5 nucleotides) 3’ . which can remove the 3' terminal nucleotide in case the polymerase makes a mistake. however. 5'-phosphodiester bond. DNA polymerase catalyzes an attack by the 3' OH on the alpha phosphate of the dGTP. .• Once the RNA primer has been synthesized. and releasing pyrophosphate. DNA polymerase can then bind and begin to synthesize DNA. which is then hydrolyzed to two molecules of inorganic phosphate. The new strand of DNA grows in a 5' to 3' direction. All DNA polymerases require a primer (or a growing DNA chain) with a free 3' OH. some DNA polymerases also have a 3' to 5' proofreading activity. forming a 3'. DNA polymerase 5’ 5’ RNA primer 3’ 5’ newly synthesized DNA 3’ . Discontinuous Synthesis Of DNA • Because DNA synthesis always proceeds in a 5' to 3' direction. The other strand has to be made "discontinuously" in short pieces (short red lines)." . and because the two DNA strands are arranged antiparallel with respect to each other. This latter strand is called the "lagging strand" while the continuously synthesized strand is called the "leading strand. only one of the two newly synthesized strands can be made "continuously" (continuous red line) as the DNA polymerase moves away from the origin of replication and more DNA template is exposed. has to be discontinuous... synthesis of one of the strands. 5’ 3’ . This is the lagging strand. ..Discontinuous synthesis of DNA 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ Because DNA is always synthesized in a 5’ to 3’ direction.. Leading And A Lagging Strand • The small pieces of DNA that comprise the lagging strand are called "Okazaki fragments." They are eventually ligated together forming a continuous DNA strand. . Each replication fork has a leading and a lagging strand leading strand (synthesized continuously) replication fork 5’ 3’ 3’ 5’ 5’ 3’ 3’ 5’ replication fork 5’ 3’ 3’ 5’ lagging strand (synthesized discontinuously) • The leading and lagging strand arrows show the direction of DNA chain elongation in a 5’ to 3’ direction • The small DNA pieces on the lagging strand are called Okazaki fragments (100-1000 bases in length) . " Note the direction (arrows) of leading strand synthesis and lagging strand synthesis (both are in a 5' to 3' direction). DNA polymerase moves continuously along the leading strand. . primase has to synthesize an RNA primer to which the DNA polymerase synthesizing the lagging strand can bind.• The next series of figures shows the process of DNA synthesis at the so-called "replication fork. As stated previously. As the template DNA unwinds. exposing the singlestranded template for the lagging strand. RNA primer direction of leading strand synthesis 3’ 5’ replication fork 5’ 3’ 3’ 5’ direction of lagging strand synthesis . which inhibit DNA gyrase. such as E. unwind them and reseal the strands. and Pseudomonas aeruginosa. Gram-negative bacteria. The increasing torsional stress needs to be dissipated in order for the fork to continue to unwind so that replication can proceed. Any DNA that is overwound (or underwound) is said to be “supercoiled. .” Overwound DNA is positively supercoiled. coli. which cut the DNA strands. can be killed by fluoroquinolone antibiotics. Topoisomerase II cuts both strands of DNA. As they do so they introduce negative supercoiling into the DNA to compensate for the positive supercoiling.Strand Separation At The Replication Fork Causes Positive Supercoiling Of The Downstream Double Helix • The strand separation process (unwinding the complementary WatsonCrick DNA strands) causes overwinding ahead of the fork. swivels them and rejoins them. and relaxes negative supercoils. This is accomplished by DNA topoisomerases. Klebsiella pneumoniae. a topoisomerase II. Topoisomerase I cuts only one strand. which breaks and reseals the DNA to introduce negative supercoils ahead of the fork • Fluoroquinolone antibiotics target DNA gyrases in many gram-negative bacteria: ciprofloxacin and levofloxacin (Levaquin) .Strand separation at the replication fork causes positive supercoiling of the downstream double helix 3’ 5’ 5’ 3’ 3’ 5’ • DNA gyrase is a topoisomerase II. opening up more DNA.Movement Of The Replication Fork • As the replication fork moves further to the left. another RNA primer has to be synthesized. . Movement of the replication fork 5’ 3’ 5’ 3’ Movement Of The Replication Fork • Each RNA primer (dashed red line) on the lagging strand then serves as a starting point for the initiation of DNA synthesis (Okazaki fragment; solid red line). Movement of the replication fork 5’ RNA primer Okazaki fragment RNA primer However. At this point. DNA polymerase I takes over. . synthsizing DNA to fill in the gap up to the next RNA primer.• E. coli DNA polymerase III initiates at the RNA primer. it falls off the template DNA once it reaches the next RNA primer. It contains a 5' to 3' exonuclease activity that can remove the RNA primer while it simultaneously adds DNA nucleotides to the 3' end of the Okazaki fragment. 3’ RNA primer 5’ pol III 5’ DNA polymerase III initiates at the primer and elongates DNA up to the next RNA primer 3’ 5’ 5’ 3’ newly synthesized DNA (100-1000 bases) (Okazaki fragment) 5’ pol I DNA polymerase I inititates at the end of the Okazaki fragment and further elongates the DNA chain while simultaneously removing the RNA primer with its 5’ to 3’ exonuclease activity . . DNA polymerase I cannot seal the gap between the two adjacent Okazaki fragments. 5'-phosphodiester bond in an ATP-dependent reaction. which catalyzes the formation of a 3'. Thus. it takes one RNA polymerase (primase). Once initiation occurs on the RNA primer. This job is carried out by DNA ligase.• However. the leading strand only requires DNA polymerase III for its synthesis. and DNA ligase to synthesize the lagging strand. two DNA polymerases (III and I). 3’ 5’ newly synthesized DNA (Okazaki fragment) DNA ligase seals the gap by catalyzing the formation of a 3’. 5’-phosphodiester bond in an ATP-dependent reaction 3’ 5’ . DNA gyrase. The unwinding itself is carried out by the Rep protein. which is a helicase. . The act of unwinding the DNA double helix puts torsional stress in the form of positive supercoils in the DNA upstream of the fork. Coli • This figure shows the proteins required for DNA synthesis at the replication fork. which is a topoisomerase II. breaks and reseals the DNA in order to introduce negative supercoils in the DNA. thus overcoming the positive supercoils. to keep the unwound strands single-stranded.Proteins At The Replication Fork In E. Finally. they bind SSB (single-strand binding protein). there are several others that act upstream of the replication fork. To overcome this. In addition to the proteins required for leading and lagging strand synthesis. this is a topoisomerase II.Proteins at the replication fork in E. which breaks and reseals double-stranded DNA to introduce negative supercoils ahead of the fork pol I . coli Rep protein (helicase) pol III 3’ 5’ 5’ 3’ G Single-strand binding protein (SSB) Primasome DNA ligase C B pol III DNA gyrase . . coli chromosome. and their activities.Components Of The Replication Apparatus • This table lists the proteins required for replication of the E. 5’-phosphodiester bond .Components of the replication apparatus dnaA Primasome dnaB dnaC dnaG DNA gyrase Rep protein SSB DNA pol III DNA pol I DNA ligase binds to origin DNA sequence helicase (unwinds DNA at origin) binds dnaB primase (synthesizes RNA primer) introduces negative supercoils ahead of the replication fork helicase (unwinds DNA at fork) binds to single-stranded DNA primary replicating polymerase removes primer and fills gap seals gap by forming 3’. and epsilon. and thus requires a 5' to 3' exonuclease activity. coli. They both have 5' to 3' polymerizing activity and 3' to 5' proofreading activity. Since it seems to lack a 3’ to 5’ exonuclease activity. Recently.Properties Of DNA Polymerases • The main DNA polymerases required for DNA replication in E. delta. It is a toroidal-shaped (donut) protein which encircles DNA and can slide bidirectionally along the duplex. by removing primers and extending the Okazaki fragment. DNA polymerase I also removes the RNA primer and is also a DNA repair enzyme. it has been discovered that PCNA also interacts with proteins involved in cell-cycle progression. it may not be able to synthesize DNA with high fidelity and thus it may not be the main lagging strand polymerase. coli are DNA polymerases I and III. human cells have at least five DNA polymerases. If not. In humans. Alpha is associated with an RNA primase and it is thought that these activities are responsible for synthesizing a short RNA-DNA primer. There is some uncertainty as to the function of alpha in lagging strand synthesis. In contrast to just three DNA polymerases in E. • • . The enzymes thought to be responsible for replication of nuclear DNA are DNA polymerases alpha. Proliferating cell nuclear antigen (PCNA) has a role in both replication and repair. there is also a requirement for DNA ligase. which is also specifically responsible for synthesis of the leading strand. One of its functions is to serve as a processivity factor for DNA polymerase delta and epsilon. the main polymerase for the lagging strand may be delta. PCNA holds the polymerase to the DNA template for rapid and processive DNA synthesis. DNA polymerase epsilon may function like the bacterial DNA polymerase I. and it is also a repair enzyme and is used in making recombinant DNA molecules • all DNA polymerases require a primer with a free 3’ OH group • all DNA polymerases catalyze chain growth in a 5’ to 3’ direction • some DNA polymerases have a 3’ to 5’ proofreading activity . coli_ Polymerization: 5’ to 3’ Proofreading exonuclease: 3’ to 5’ Repair exonuclease: 5’ to 3’ pol I pol II pol III (core) yes yes yes yes yes yes yes no no DNA polymerase III is the main replicating enzyme DNA polymerase I has a role in replication to fill gaps and excise primers on the lagging strand.Properties of DNA polymerases DNA polymerases of E. ." which are base pair mutations or small deletions or insertions.Mutation • This slide shows the three basic types of mutational events and their frequencies. We will be concentrating on "gene mutations. Mutation Types and rates of mutation Type Genome mutation Chromosome mutation Gene mutation Mechanism chromosome missegregation (e.g.. aneuploidy) chromosome rearrangement (e..g. point mutation. or small deletion or insertion Frequency________ 10-2 per cell division 6 X 10-4 per cell division 10-10 per base pair per cell division or 10-5 ..g. translocation) base pair mutation (e.10-6 per locus per generation . 5 43 32 2 44 60 5 to 40 to 5 to 105 to 57 to 3 to 100 to 120 to 12 *mutation rates (mutations / locus / generation) can vary from 10-4 to 10-7 depending on gene size and whether there are “hot spots” for mutation (the frequency at most loci is 10-5 to 10-6 ). .Mutation rates* of selected genes Gene Achondroplasia Aniridia Duchenne muscular dystrophy Hemophilia A Hemophilia B Neurofibromatosis -1 Polycystic kidney disease Retinoblastoma New mutations per 106 gametes 6 2. at a rate of production of ~80 million sperm per day. a normal ejaculate has ~100 million sperm. ~1 in 10 sperm carries a new deleterious mutation. a male will produce a sperm with a new mutation in the Duchenne muscular dystrophy gene approximately every 10 seconds.Many Polymorphisms Exist In The Genome • What is the frequency of new germline mutations? Consider the following: each sperm contains ~100 new mutations. . 100 X 100 million = 10 billion new mutations. 8 million differences per haploid genome • polymorphisms were caused by mutations over time • polymorphisms called single nucleotide polymorphisms (or SNPs) are being catalogued by the Human Genome Project as an ongoing project .Many polymorphisms exist in the genome • the number of existing polymorphisms is ~1 per 500 bp • there are ~5. (Note that a transition mutation results when a pyrimidine on one strand is converted to another pyrimidine on the same strand.Types Of Base Pair Mutations • This slide illustrates the four basic types of base pair mutations. Two of them result in the conversion of one base pair to another (base pair substitution). The others result in removal (deletion) or addition (insertion) of one or more base pairs.) . The complementary strand would see a conversion from one purine to the other purine. Types of base pair mutations CATTCACCTGTACCA GTAAGTGGACATGGT CATCCACCTGTACCA GTAGGTGGACATGGT transition (T-A to C-G) normal sequence CATGCACCTGTACCA GTACGTGGACATGGT transversion (T-A to G-C) base pair substitutions transition: pyrimidine to pyrimidine transversion: pyrimidine to purine CATCACCTGTACCA GTAGTGGACATGGT deletion CATGTCACCTGTACCA GTACAGTGGACATGGT insertion deletions and insertions can involve one or more base pairs . The common forms of adenine and cytosine are the amino forms. The repositioning of hydrogens changes their base pairing. . hydrogen bonding chemistry.Spontaneous Mutations Can Be Caused By Tautomers • There are many different causes of mutations. Spontaneous mutations (those that result from no external cause) can occur simply by rearrangement of bonds and by the repositioning of hydrogens in the purine and pyrimidine bases. which can rearrange to the imino forms. Spontaneous mutations can be caused by tautomers Tautomeric forms of the DNA bases Adenine Cytosine AMINO IMINO . Tautomeric Forms Of The DNA Bases • The common forms of guanine and thymine are the keto forms. . which can rearrange to the enol forms. Tautomeric forms of the DNA bases Guanine Thymine KETO ENOL . the wrong nucleotide will be inserted into the growing DNA chain.Mutation Caused By Tautomer Of Cytosine • This figure illustrates how a conversion from the amino to the imino form of cytosine changes the locations of hydrogen donor and acceptor groups. the enol form of guanine looks like an adenine and should be able to form three hydrogen bonds with thymine. such that the imino form of cytosine base pairs with adenine instead of guanine. and the enol form of thymine looks like a cytosine and should be able to form three hydrogen bonds with guanine. In all cases. As for the other tautomers. . this will ultimately lead to a transition mutation. As shown in the next figure. the imino form of adenine "looks sort of like" a guanine and should be able to form two hydrogen bonds with cytosine. Mutation caused by tautomer of cytosine Cytosine Normal tautomeric form Cytosine Guanine Rare imino tautomeric form Adenine • cytosine mispairs with adenine resulting in a transition mutation . If the tautomeric form of cytosine is present during DNA replication. an adenosine will be inserted into the daughter DNA strand (instead of the normal guanosine). the adenosine then serves as a template for the insertion of a thymidine in the new DNA strand. During the next round of DNA replication. .Mutation Is Perpetuated By Replication • The conversion of a C-G base pair to a T-A base pair takes two steps. resulting in a transition mutation (the conversion of a C-G to a T-A). or if improperly repaired .Mutation is perpetuated by replication C G C G C G C A • replication of C-G should give daughter strands each with C-G • tautomer formation C during replication will result in mispairing and insertion of an improper A in one of the daughter strands C A T A • which could result in a C-G to T-A transition mutation in the next round of replication. .Chemical Mutagens • Mutation can also occur by the action of chemical mutagens. and how the oxidative deamination of adenine converts it to hypoxanthine. This figure shows how oxidative deamination of cytosine converts it to uracil. both processes altering the hydrogen bonding specificities of these bases. Chemical mutagens Deamination by nitrous acid . which can be cleaved by oxygen free radicals and break the phosphodiester backbone of DNA. .Attack By Oxygen Free Radicals Leading To Oxidative Damage • The deoxyribose ring is also susceptible to damage. Attack by oxygen free radicals leading to oxidative damage • many different oxidative modifications occur • by smoking. etc. • 8-oxyG causes G to T transversions O H N O NH N NH NH2 O N NH NH N NH2 guanine 8-oxyguanine (8-oxyG) • the MTH1 protein degrades 8-oxy-dGTP preventing misincorporation • mutation of the MTH1 gene causes increased tumor formation in mice . reversion to His+ may occur • reversion is correlated with carcinogenicity .Salmonella typhimurium cannot grow without histidine • if test compound is mutagenic.Ames test for mutagen detection • named for Bruce Ames • reversion of histidine mutations by test compounds • His. The thymine dimer bridges two adjacent thymine residues on the same DNA strand . This figure shows the formation of a thymine dimer.Thymine Dimer Formation By UV Light • Sunlight is particularly damaging to DNA. catalyzed by UV light. Thymine dimer formation by UV light . DNA Lesions • As shown here. any of which can alter DNA function and cause mutations if not repaired. DNA is prone to many different kinds of damaging reactions. . mitomycin C Spontaneous and transient Deletion-insertion Dimer formation Strand breaks Interstrand cross-links Tautomer formation .Summary of DNA lesions Missing base Altered base Incorrect base Acid and heat depurination (~104 purines per day per cell in humans) Ionizing radiation. chemicals (bleomycin) Psoralen derivatives. alkylating agents Spontaneous deaminations cytosine to uracil adenine to hypoxanthine Intercalating reagents (acridines) UV irradiation Ionizing radiation. 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 mismatch (post-replication) repair followed by excision repair • Mutations that occur spontaneously any time are repaired by excision repair (base excision or nucleotide excision) . the newly synthesized DNA is methylated on certain adenine bases.Mismatch (Post-replication) Repair (Reduces DNA Replication Errors 1. however. if a mutation occurs in the new strand. Once some time has passed. the repair machinery can tell which is the template strand (presumable the correct strand) and the new strand (containing the mutation). . It will then repair the mismatch by excision repair. There are six mismatch repair genes that can be affected in HNPCC.000-fold) • For DNA to be repaired properly following the misincorporation of a nucleotide into the newly synthesized DNA strand. does not occur right away . Case 13). After DNA replication takes place. the new strand will also become methylated. This. Thus.there is a "window of time" in which the newly synthesized DNA (in red) is not methylated. the replication machinery must have a means by which to distinguish between the "old" (template) strand shown in black and the "new" (daughter) strand shown in red. Defects in mismatch repair are a cause of hereditary nonpolyposis colon cancer (Thompson & Thompson. at that point it will not be possible to distinguish the correct nucleotide from the incorrect nucleotide at the site of a base pair mismatch. Mismatch (post-replication) repair (reduces DNA replication errors 1.000-fold) • the parental DNA strands are methylated on certain adenine bases CH3 CH3 5’ 3’ CH3 • mutations on the newly replicated strand are identified by scanning for mismatches prior to methylation of the newly replicated DNA • the mutations are repaired by excision repair mechanisms • after repair. the newly replicated strand is methylated CH3 . Excision Repair • • There are two types of excision repair: base excision repair (left) and nucleotide excision repair (right). and the space is opened up by repair nucleases that remove a number of nucleotides from one strand (the other strand has to be left intact to serve as the template for DNA repair). The repair polymerase. the U can be recognized as being an improper base in DNA by the enzyme. because the template strand always contains the information for the synthesis of a complementary strand. a special repair excinuclease removes about 30 nucleotides. This enzyme cleaves the uracil base from the phosphodiester backbone. If cytosine is deaminated forming uracil. • . The double strandedness of DNA makes possible both DNA replication and DNA repair. While they differ in their initial steps (top). uracil DNA glycosylase. they are similar in the latter steps (bottom). The DNA is then resynthesized and ligated together as with base excision repair. for example when there is a thymine dimer. Nucleotide excision repair occurs when the DNA lesion is larger. In this case. including the lesion. DNA polymerase beta. then fills in the gap and DNA ligase seals the last phosphodiester bond. deamination Excision repair ATGCUGCATTGA TACGGCGTAACT uracil DNA glycosylase thymine dimer ATGC GCATTGA TACGGCGTAACT AT GCATTGA TACGGCGTAACT ATGCCGCATTGA TACGGCGTAACT DNA ligase repair nucleases ATGCUGCATTGATAG TACGGCGTAACTATC excinuclease DNA polymerase β AT (~30 nucleotides) AG TACGGCGTAACTATC DNA polymerase β ATGCCGCATTGATAG TACGGCGTAACTATC DNA ligase ATGCCGCATTGA TACGGCGTAACT Base excision repair ATGCCGCATTGATAG TACGGCGTAACTATC Nucleotide excision repair . It is believed that this methylation functions to regulate gene expression because 5-methylcytosine (5mC) residues are often clustered near the promoters of genes in so-called "CpG islands." The problem that arises from these methylations is that subsequent deamination of a 5mC results in the production of thymine.Deamination Of Cytosine Can Be Repaired • Deaminated cytosine is fairly straightforward to repair because uracil is recognized as being "foreign" in the DNA molecule. However. it does not know which of the two strands to repair (50% of the time it will make the right choice and 50% of the time it will make the wrong choice). while a base pair mismatch is seen in the DNA by the repair machinery. Thus. many cytosines are reversibly methylated at CG sites (or CpG sites to emphasize that the C and G are adjacent nucleotides on the same DNA strand). . 5'-mCG-3' sites are "hot-spots" for mutation. which is not foreign to DNA. As such. Deamination of cytosine can be repaired cytosine uracil Deamination of 5-methylcytosine cannot be repaired 5’-methylcytosine thymine More than 30% of all single base changes that have been detected as a cause of genetic disease have occurred at 5’-mCpG-3’ sites . Correlation Between DNA Repair Activity And The Life Span Of The Organism • There is a direct correlation between DNA repair enzymatic activity and the life span of organisms. 601. pg. suggesting that DNA repair activity slows down cellular senescence and that cellular senescence is caused by mutations in DNA. . See Baynes & Dominiczak. Defects in DNA repair or replication can lead to a number of abnormalities. Correlation between DNA repair activity in fibroblast cells from various mammalian species and the life span of the organism 100 human elephant cow Life span 10 hamster rat mouse shrew 1 DNA repair activity . See Baynes & Dominiczak. . 315.Defects In DNA Repair Or Replication • As shown here. there are a number of defects of DNA replication and repair that are associated with a predisposition to cancer and other disorders. pg. This highlights the importance of high fidelity DNA replication and for the presence of DNA repair mechanisms for normal cell function and longevity. particularly leukemias • Xeroderma pigmentosum • caused by mutations in genes involved in nucleotide excision repair • associated with a >1000-fold increase of sunlight-induced skin cancer and with other types of cancer such as melanoma • Ataxia telangiectasia • caused by gene that detects DNA damage • increased risk of X-ray • associated with increased breast cancer in carriers • Fanconi anemia • caused by a gene involved in DNA repair • increased risk of X-ray and sensitivity to sunlight • Bloom syndrome • caused by mutations in a a DNA helicase gene • increased risk of X-ray • sensitivity to sunlight • Cockayne syndrome • caused by a defect in transcription-linked DNA repair • sensitivity to sunlight • Werner’s syndrome • caused by mutations in a DNA helicase gene • premature aging .Defects in DNA repair or replication All are associated with a high frequency of chromosome and gene (base pair) mutations. most are also associated with a predisposition to cancer.