DNA Replication and Repair 2023 PDF

DNA Replication 5BC001 Mark Morris troductory Video of DNA Replication: https://www.youtube.com/watch?v=TNKWgcFPHqw (3 min) Two antiparallel strands are held together by hydrogen bonding between complimentary bases: A-T C-G Chargaff’s rule...

DNA Replication 5BC001 Mark Morris troductory Video of DNA Replication: https://www.youtube.com/watch?v=TNKWgcFPHqw (3 min) Two antiparallel strands are held together by hydrogen bonding between complimentary bases: A-T C-G Chargaff’s rule 5’ 3’ 3’ 5’ Alberts Mol Bio Cell  DNA Is a Double Helix consisting of two polynucleotide chains that run antiparallel. Lewin chapter 1 Albert chapter 4 Nucleotides form long chains by 5’-3’ phosphodiester bonds: B-DNA: Supercoiled DNA: This is the most common form of DNA and the one This is a more compact structure that forms when most often depicted in textbooks and popular the DNA helix is subjected to strain by being media. overwound or underwound. Right-handed double helix. Plays a role in the compaction of DNA in cells and Has about 10.5 base pairs (bp) per turn. also has implications in DNA replication and Major and minor grooves are well-defined. transcription. A DNA B DNA Z DNA  1957: Meselson–Stahl experiment As the Watson-Crick structure suggests, DNA replication is semi-conservative DNA replication is semiconservative, producing one newly made strand pared with each older strand Refer to 4BC003 lectures Alberts chapter 5 Enzymes Required for DNA Replication 1. DNA helicases - disruption of hydrogen bonds between the two strands and separate DNA by "unzipping” mechanism 2. Topoisomerase - elimination of all the topological links between the two strands and to facilitate unwinding (swivel motion) 3. DNA Primase – synthesizes RNA primer to initiate DNA replication 4. DNA Polymerase – Synthesis of new strand of DNA complementary to the template DNA 5. DNA Ligase – facilitates joining of DNA strands by formation of phosphodiester bonds DNA replication is Semiconservative AND Semidiscontinuous (the lagging strand is not copied continuously): DNA is made 5’ to 3’ which is fine for on side of the DNA Lewin Chapter 1 A note on AI!  DNA Primase: RNA Primers to Start the DNA Polymerse Off DNA polymerases require a free 3’OH group to add onto Therefore DNA PRIMASE adds little RNA primers to the DNA (which are later removed) Why not just use DNA that does not need to be removed…? DNA polymerase has exonuclease activity and cannot start polymerizing directly Primase has no self-correcting mechanism but can initiate polymerization… introduces many errors that are then removed by DNA Pol. Alberts Figure 5.4 DNA synthesis catalyzed by DNA polymerase. (A) DNA polymerase catalyzes the stepwise addition of a deoxyribonucleotide to the 3ʹ-OH end of a polynucleotide chain, the growing primer strand that is paired to an existing template strand. The newly synthesized DNA strand therefore polymerizes in the 5ʹ-to-3ʹ direction as shown also in the previous figure. Because each incoming deoxyribonucleoside triphosphate must pair with the template strand to be recognized by the DNA polymerase, this strand determines which of the four possible deoxyribonucleotides (A, C, G, or T) will be added. The reaction is driven by a large, favorable free-energy change, caused by the release of pyrophosphate and its subsequent hydrolysis to two molecules of inorganic phosphate. (B) Structure of DNA polymerase complexed wth DNA (orange), as determined by x-ray crystallography (Movie 5.1). The template DNA strand is the longer strand and the newly synthesized DNA is the shorter. (C) Schematic diagram of DNA polymerase, based on the structure in (B). The proper base-pair geometry of a correct incoming deoxyribonucleoside triphosphate causes the polymerase to tighten around the base pair, thereby initiating the nucleotide addition reaction (middle diagram (C)). Dissociation of pyrophosphate relaxes the Origin of replication Prokaryotic Eukaryotic DNA replication occurs in both directions  DNA replication starts at specific locatio Origin of Replication in Eukaryotes Origins of replication one DNA strand Replication fork ey problems to overcome: Replication must occur with extreme accuracy Every nucleotide must be replicated only once Origins od replication in procaryotes have well defined consensus sequences, In eukaryotes they are less conserved. Two DNA strands  Process of DNA Replication 1. Initiation Proteins (Pre-replicative complex) Are bound to Ori waiting for signaling to initiate replication (see cell cycle lecture) 2. Elongation Origin of Replication (Ori) 3. Termination 1. Initiation see cell cycle lecture for full detail Helicase! Process of DNA Replication: initiation simplified schematic: Replisome Replication initiates when a protein complex binds to the origin and “melts” the DNA there (opens up a replication bubble) Copyright © 2013 by Jones & Bartlett Lewin Chapter 11 Learning, LLC an Ascend Learning Company Initiation DNA helicases - disruption of hydrogen bonds between the two strands and separate DNA by "unzipping” mechanism For DNA synthesis to proceed, the DNA double helix must be opened up (“melted”) ahead of the replication fork so that the incoming deoxyribonucleoside triphosphates can form base pairs with the template strands. However, the DNA double helix is very stable under physiological conditions; the base pairs are locked in place so strongly that it requires temperatures approaching that of boiling water to separate the two strands in a test tube. For this reason, two additional types of replication proteins—DNA helicases and single- strand DNA-binding proteins—are needed to open the double helix and provide the appropriate single-strand DNA templates for the DNA polymerase to copy. DNA helicases use ATP to propel themselves rapidly along a DNA single strand. When they encounter a region of double helix, they continue to move along their strand, thereby prying apart the helix at rates of up to 1000 nucleotide pairs per second Helicase needs some single stranded DNA to get starte This is provided by cdc6 and cdt1 Single-strand DNA-binding proteins AKA: Helix destabilizing proteins bind to the single stranded DNA behind helicase to prevent the DNA strands reforming double strands: This also prevents hairpins forming and Still allows DNA polymerase to recognize the individual basepairs: Figure 5.16 Human single-strand binding protein bound to DNA The DNA bases remain exposed in this protein–DNA complex. DNA Topoisomerase - topoisomerase I, produces a transient single-strand break; this break in the phosphodiester backbone allows the two sections of DNA helix on either side of the nick to rotate freely relative to each other, using the phosphodiester bond in the strand opposite the nick as a swivel point (Figure 5.21). Any tension in the DNA helix will drive this rotation in the direction that relieves the tension. As a result, DNA replication can occur with the rotation of only a short length of helix—the part just ahead of the fork. Alberts Figure 5.21 The reversible DNA nicking reaction catalyzed by a eukaryotic DNA topoisomerase I enzyme. DNA polymerase 5’ 3’ direction E. coli Three types of polymerase I mainly used for filling in small DNA segments during repair or replication (removed RNA primer (5’-3’ exonuclease) II precise function unclear but may substitute for DNA polymerase I III the main enzyme of DNA replication (5’-3’ Polymerase)  Separate Eukaryotic DNA Polymerases undertake Initiation and Elongation A replication fork has one complex of DNA polymerase α/primase, one complex of DNA polymerase δ, and one complex of DNA polymerase ε. The DNA polymerase α/primase complex initiates the synthesis of both DNA strands. DNA polymerase ε elongates the leading strand and a second DNA polymerase δ elongates the lagging Lewin, strand. Chapter 11  Essential Viewing: https://www.youtube.com/watch?v=0Ha9npp A sliding clamp protein keeps DNA Pol III Attached to the replication fork: This increases it’s processivity Replisome: Bacterial Vs Eukaryote Names of Enzymes  DNA Polymerases A bacterium or eukaryotic cell has several different DNA polymerase enzymes One DNA polymerase (a DNA replicase) undertakes semiconservative replication; the others are involved in repair reactions Only one DNA polymerase is the replication enzyme. Lewin, Chapter 18 Essential Viewing: https://www.youtube.com/watch?v=QMX7IpME7X8 Prokaryotic Replicasome (V similar to Eucaryotic) Each catalytic core of Pol III synthesizes a daughter strand. DnaB is responsible for forward movement at the replication fork. Lewin, Chapter 18 Read Alberts Chapter 5!  DNA ligase Following the removal or the RNA primer by DNA Pol I (5’-3’ exonuclease activity) DNA Ligase catalyses the formation of a phosphodiester bond between the 3’-hydroxyl group at the end of one DNA chain and the 5’- DNA Repair 5BC001 Mark Morris DNA Polymerase Makes mistakes at the replication fork 1 per 100 thousand base pairs Base pairing errors occur relatively commonly Eg: But it can correct them! Pol III has 3’ to 5’ exonuclease activity (correcting as it goes) Error rate now every billion base pairs (1 in every 109) Pol II has 5’ to 3’ exonuclease activity (eg for removing RNA primer) If the DNA polymerase did nothing when a mispairing occurred between an incoming deoxyribonucleoside triphosphate and the DNA template, the wrong nucleotide would often be incorporated into the new DNA chain, producing frequent mutations. The high fidelity of DNA replication depends not only on the initial base-pairing but also on several “proofreading” mechanisms. The error-correcting reaction, known as exonucleolytic proofreading, occurs immediately after an incorrect nucleotide is covalently added to the growing chain. DNA polymerase enzymes require a previously formed, base-paired 3ʹ-OH end of a primer strand to allow elongation. Those DNA molecules with a mismatched (improperly base- paired) nucleotide at the 3ʹ-OH end of the primer strand are not effective as templates because the polymerase has difficulty extending such a strand. DNA Pol correct such a mismatched primer strand by means of a separate catalytic site. This 3ʹ-to-5ʹ proofreading exonuclease clips off any unpaired or mispaired residues at the primer terminus, continuing until enough nucleotides have been removed to regenerate a correctly base- paired 3ʹ-OH terminus that can prime DNA synthesis. DNA POL has 3’-5’ exonuclease activity: This removes inappropriately paired bases: Figure 5-8 (part 1 of 2) Molecular Biology of the Cell (© Garland Science 2008) P: Polymerization catalytic site E: Exonucleolytic catalytic site Strand-directed mismatch repair Removes errors not fixed by DNA pol exonuclease: Identifies distortions in DNA caused by the presence of no-complimentary bases Nicks are common in newly synthesis DNA. This allows identification of which strand the error has occurred in MutS in humans = MHS2 MutL in humans=MLH1 Strand is removed by a specific exonuclease: Exo1 DNA polymerase fills in the gap DNA Ligase forms a phosphodiester bond between the 3’ end of the newly synthesized section and the 5’ end of the existing strand Figure 5-20a Molecular Biology of the Cell (© Garland Science 2008) Figure 5.19 Strand-directed mismatch repair. (A) The two proteins shown are present in both bacteria and eukaryotic cells: MutS binds specifically to a mismatched base pair, while MutL scans the nearby DNA for a nick. Once MutL finds a nick, it triggers the degradation of the nicked strand all the way back through the mismatch. Because nicks are largely confined to newly replicated strands in eukaryotes, replication errors are selectively removed. In bacteria, an additional protein in the complex (MutH) nicks unmethylated (and therefore newly replicated) GATC sequences, thereby beginning the process illustrated here. In eukaryotes, MutL contains a DNA nicking activity that aids in the removal of the damaged strand. (B) The structure of the MutS protein bound to a DNA mismatch. This protein is a dimer, which grips the DNA double helix as shown, kinking the DNA at the mismatched base pair. It seems that the MutS protein scans the DNA for mismatches by testing for  There are 100s of gene products (proteins) involved in DNA repair Inheriting mutations in genes required DNA repair result in serious syndromes: Exo1 Table 5-2 Molecular Biology of the Cell (© Garland Science 2008) Controlling the Direction of Mismatch Repair The mut genes code for a mismatch-repair system that deals with mismatched base pairs. There is a bias in the selection of which strand to replace at mismatches The strand lacking methylation at a hemimethylated GATC/CTAG is usually replaced – because this is the “new” strand This repair system is used to remove errors in a newly synthesized strand of DNA. At G-T and C-T mismatches, the T is preferentially removed. mutator : a gene whose mutation results in an increase in the basal level of mutation of the genome. Such genes are often code for proteins that are involved in repairing damaged DNA.  Methylation tells the enzymes what the new strand is DAM= GATC sequences are DNA adenine methyltransferase targets for the Dam methylase after replication. During the period before this methylation occurs, the nonmethylated strand is the target for repair of mismatched bases. prokaryotes Lewin, Chapter 14  MutS checks methylation to work out which is the “wrong” or newly made strand MutS recognizes a mismatch and translocates to a GATC site. MutH cleaves the unmethylated strand at the GATC. Endonucleases degrade the strand from the GATC to the mismatch site. Lewin, Chapter 14  Replication slippage, also known as strand slippage, refers to a phenomenon that occurs during DNA replication when the DNA polymerase temporarily dissociates from the template strand and the newly synthesized strand misaligns. This misalignment usually happens at repetitive DNA sequences The MutS/MutL system initiates repair of mismatches produced by replication slippage. Lewin, Chapter 14 aneous DNA base changes occur after polymeriz The DNA of each human cell loses about 18,000 purine bases (adenine and guanine) every day because their N-glycosyl linkages to deoxyribose hydrolyze, a spontaneous reaction called depurination. Spontaneous deamination of cytosine to uracil in DNA occurs at a rate of about 100 bases per cell per day At next DNA replication this base may be removed completely (v BAD for genes) At next DNA replication this base may be read as a T and on the opposite strand an A incorporated (A point mutation) (see next slide)  Depurination removes a base from DNA, blocking replication and transcription. Lewin, Chapter 14  What causes mutations Chemical mutagens: Deamination (induced by HNO2, nitrous acid) SAM: S-adenosyl methionine Dnmt: DNA Methyl-transferase Error Consiquence Error Consiquence What causes mutations Chemical mutagens: Alkylating agents add an alkyl group (CH3-, CH3CH2-) to a base, causing base substitutions or strand breakage. Alkylating agents 5’ ATGCAGTTAG 3’ 5’ ATGCAGTTAG 3’ 3’ TATGTGAATC 5’ 5’ ATATGCAGTTAG 3’ 3’ TATGTCAATC 5’ 5’ ATACAGTTAG 3’ 3’ TATACGTCAATC 5’ 5’ ATGCAGTTAG 3’ 3’ TATGTCAATC 5’ 5’ ATATGCAGTTAG3’ 3’ TACGTCAATC 5’ 3’ TATACGTCAATC5’ 5’ ATGCAGTTAG 3’ 5’ ATGCAGTTAG 3’ 3’ TACGTCAATC 5’ 3’ TACGTCAATC 5’ 5’ ATGCAGTTAG 3’ 3’ TACGTCAATC 5’  Lewin, Chapter 14 What causes mutations: Base dimerization Dimers of adjacent bases form following exposure to UV irradiation T T f left uncorrected when the DNA is replicated, most Covalent linkage of these changes would be expected to lead either to the deletion of one or more base pairs or to a T base-pair substitution in the daughter DNA chain T Alberts, Chapter 5 The most common type of thymine dimer. This type of damage occurs in the DNA of cells exposed to ultraviolet irradiation (as in sunlight). A similar dimer will form between any two neighboring pyrimidine  DNA Damage Can Be Removed by More Than One Pathway Two ase of theRepair excision most (BER) Nucleotide common pathways are: excision Repair (NE In both: -The damage is excised -The original DNA sequence is restored by a DNA polymerase that uses the undamaged strand as its template. -The remaining break in the double helix is sealed by DNA ligase ase excision Repair (BER) Involves a battery of enzymes called DNA glycosylases. eg Each glycosylase recognize a specific type of altered base in DNA and catalyze its hydrolytic removal. There are at least six types of these enzymes, including those that remove deaminated Cs, deaminated As, different types of alkylated or oxidized bases, bases with opened rings, and bases in which a carbon–carbon double bond has been accidentally converted to a carbon–carbon single bond. an altered base detected by an enzyme-mediated “flipping-out” of the altered nucleotide from the helix, which allows the DNA glycosylase to probe all faces of the base for damage These enzymes travel along DNA using base- DNA glycosylase enzymes recognizes specific inappropriate bases. Each enzyme cleaves the glycosyl bond that connects a particular recognized base (yellow) to the backbone sugar, removing it from the DNA. β (beta): DNA Polymerase δ (delta) and ε (epsilon): The “missing tooth” created by DNA glycosylase action is recognized by an enzyme called AP endonuclease (AP for apurinic or apyrimidinic, endo to signify that the nuclease cleaves within the polynucleotide chain), which cuts the phosphodiester backbone, after which the resulting gap is repaired by DNA Polymerase: Nucleotide excision Repair (NER) Repairs the damage caused by almost any large change in the structure of the DNA double helix. Such “bulky lesions” include: Those created by the covalent reaction of DNA bases with large hydrocarbons (such as the carcinogen benzopyrene, found in tobacco smoke, e coal tar, and diesel exhaust) g Various pyrimidine dimers (T-T, T-C, and C-C) caused by sunlight. A large multienzyme complex scans the DNA for a distortion in the double helix, rather than for a specific base change. Once it finds a lesion, it cleaves the phosphodiester backbone of the abnormal strand on both sides of the distortion DNA helicase peels away the single-strand oligonucleotide containing the lesion. The large gap produced in the DNA helix is then repaired by  READ Chapter 14. Excision Repair Systems in E. coli LEWIN’S Genes The term "Uvr" is derived from "UV radiation sensitive," as mutations in these genes render the bacteria more sensitive to DNA damage caused by ultraviolet (UV) radiation.  The Uvr system makes incisions ~12 bases apart on both sides of damaged DNA, removes the DNA between them, and resynthesizes new DNA.  Excision repair systems vary in their specificity, but share the same general features. Each system removes mispaired or damaged bases from DNA and then synthesizes a new stretch of DNA to replace them.  incision : an endonuclease recognizes the damaged area in the DNA, and isolates it by cutting the DNA strand on both sides of the damage.  excision : a 5’-3’ exonuclease removes a stretch of the damaged strand.  Excision-repair removes and replaces a stretch of DNA that includes the damaged base(s). Lewin, Chapter 14  The Uvr system operates in stages in which UvrA/B recognizes damage, UvrBC nicks the DNA (creates an incision), and UvrD unwinds the marked region (a helicase). The uvr system of excision repair includes three genes, uvrA, B, and C, which code for the components of a repair endonuclease. UvrD is a helicase. In almost all (99%) of cases, the average length of replaced DNA is ∼12 nucleotides Lewin, Chapter 14 In humans, the equivalent system to the Uvr-mediated nucleotide excision repair (NER) pathway involves different and more numerous components than in prokaryotes. The main components involved in human NER: 1. Damage Recognition: - XPC (in complex with RAD23B and CETN2) recognizes the DNA damage globally throughout the genome. 2. Damage Verification: Once the damage is recognized, XPA verifies the presence of the damage and stabilizes the DNA around the lesion. RPA (replication protein A) also binds to the single-stranded DNA regions to stabilize them. 3. DNA Unwinding: The TFIIH complex, which contains the helicases XPB and XPD, unwinds the DNA around the lesion to allow for incision. 4. Incision: The endonucleases XPF-ERCC1 and XPG introduce cuts in the DNA strand containing the damage. XPF-ERCC1 makes the incision 5' to the lesion, and XPG makes the incision 3' to the lesion. 5. Gap-filling and Ligation: After the removal of the damaged oligonucleotide, DNA synthesis fills in the gap, primarily by DNA polymerase δ or ε in conjunction with the replication factors RFC and PCNA. DNA ligase I or III then seals the nick, completing the repair. While the core process is similar to the prokaryotic Uvr system, the human NER pathway Lewin FIGURE 14.12 Nucleotide excision repair occurs via two major pathways: global genome repair, in which XPC recognizes damage anywhere in the genome, and transcription- coupled repair, in which the transcribed strand of active genes is preferentially repaired and the damage is recognized by an elongating RNA polymerase. Data from E. C. Friedberg, et al., Nature Rev. Cancer 1 (2001): 22–23.  DNA double strand breaks are repaired by: onhomologous End Joining (NHEJ) Homologous Recombination (HR) “Quick and dirty” Changes sequence! Restores the original sequence! a cell from a 70 year old contains ~2000 NHEJ “scars” Nonhomologous end joining alters the original DNA sequence when repairing a broken chromosome. The initial degradation of the broken DNA ends is important because the nucleotides at the site of the initial break are often damaged and cannot be ligated. Nonhomologous end joining usually takes place when cells have not yet duplicated their DNA. (B) Repairing double-strand breaks by homologous recombination is more difficult to accomplish but restores the original DNA sequence. It typically takes Mechanism of nonhomologous end joinin See Lewin Chapter 14 Fig 26 Two Ku proteins Ku70 and Ku80 form A heterodimer at DS DNA break FIGURE 14.26 Nonhomologous end joining. The blue dot on one of the two double-strand break ends signifies a nonligatable end (a). The double- strand break ends are bound by the Ku heterodimer (b). The Ku–DNA complexes are juxtaposed (c) to bridge the ends, and the gap is filled in by processing enzymes and Pol lambda or Pol mu. The ends are ligated by the specialized DNA ligase LigIV with its partner XRCC4 (d) to Double-strand breaks (DSBs) are among the most deleterious types of DNA damage, as they can lead to large deletions, chromosomal rearrangements, and genome instability if not repaired correctly. Various factors and conditions can induce DSBs: 1. **Ionizing Radiation**: Sources like X-rays, gamma rays, and cosmic rays can cause DSBs directly by breaking both DNA strands or indirectly by generating reactive oxygen species (ROS) that attack the DNA. 2. **Chemical Agents**: - **Anticancer drugs**: Some chemotherapy agents, such as bleomycin, work by inducing DSBs in tumor cells. - **Topoisomerase II poisons**: Drugs like etoposide and doxorubicin stabilize the intermediate complex formed by topoisomerase II during its action on DNA, resulting in DSBs. 3. **Ultraviolet (UV) Radiation**: While UV primarily induces pyrimidine dimers, if two closely spaced lesions are present on opposite DNA strands, they can be converted to DSBs during repair processes. 4. **Reactive Oxygen Species (ROS)**: By-products of cellular metabolism, especially during oxidative phosphorylation, ROS can attack DNA and generate various types of damage, including DSBs. 5. **Replication Fork Collapse**: Obstacles to DNA replication, such as unrepaired DNA lesions or tightly bound protein complexes, can lead to stalling and subsequent collapse of replication forks, resulting in DSBs. 6. **Mechanical Stress on DNA**: Overwinding or underwinding of DNA due to supercoiling can cause strain that leads to DSBs. 7. **Retroviral Integration**: Some retroviruses integrate their DNA into the host genome, a process that can introduce DSBs. 9. **Programmed DSBs in Meiosis**: DSBs are deliberately introduced during the early stages of meiosis to promote genetic recombination between homologous chromosomes. omologous Recombination (HR) This is the preferred method for repairing DNA double-strand breaks that arise shortly after the DNA has been replicated, while the daughter DNA molecules are still held close together. In general, homologous recombination can be regarded as a flexible series of reactions, with the exact pathway differing from one case to the next. For example, the length of the repair “patch” can vary considerably depending on the extent of 5ʹ processing and new DNA synthesis, indicated in green. one of the damaged strands can use the complementary strand of the intact DNA duplex as a template for repair. The ends of the broken DNA are chewed back, or “resected,” by specialized nucleases to produce overhanging, single-strand 3ʹ ends. The next step is strand exchange, during which one of the single- strand 3ʹ ends from the damaged DNA molecule worms its way into the template duplex and searches it for homologous sequences through base-pairing. Once stable base-pairing is established, a DNA polymerase extends the invading strand by using the information provided by the undamaged template molecule, thus restoring the damaged DNA. The last steps—strand displacement, further repair synthesis, and ligation—restore the two original DNA double helices exchange is facilitated and complete the repairbyprocess. a protein called RecA in E. coli and Rad51 in eukaryotes The Intrinsic apoptotic pathway Genes/proteins DNA Damage ATM:ATAXIA-TELANGIECTASIA MUTATED ATR: ATAXIA-TELANGIECTASIA AND RAD3-RELATED CHK1: CELL CYCLE CHECKPOINT KINASE 1 CHK2: CELL CYCLE CHECKPOINT KINASE 2 BCL2: B-cell lymphoma 2 BAX: BCL2-ASSOCIATED X PROTEIN PUMA: p53-UPREGULATED MODULATOR OF APOPTOSIS AT ATR M CHK2 CHK1 Permeabilized mitochondrial membrane leads P P to Caspase p53 activation (TF) Caspase 3, 6, 7 (cysteine-aspartic acid protease) BCL Apoptosis inducing genes proteolysis 2 inhibitor of apoptosis signaling (overexpresses/activated in many cancers) Apoptosis All of these genes have been found mutated/switched off in cancer DNA Damage If possible, the cell will attempt to repair the DNA damage Involving proteins such as AT ATR M CHK2 CHK1 P P p53 (TF) P P BRCA1/ 2 RAD51 RAD5 1 DNA repair Apoptosis  Ataxia telangiectasia Recessive inherited syndrome (2 mutant copies of ATM gene) Ataxia: Poor coordination Telangiectasia: Small dilated blood vessels Weakened immune system Radiosensitive- High risk of lymphoma and leukemia A good reference video. https://www.youtube.com/watch?v=vP8-5Bhd2ag 3min) This covers the main DNA damage repair systems but does not specify proteins involved (watch it and use your lecture notes to Identify the proteins involved. Extra material to read http://www.mhhe.com/biosci/cellmicro/weavermolbio/dna1.mhtml http://chemistry.elmhurst.edu/vchembook/655cancer2.html https://www.youtube.com/watch?v=vP8-5Bhd2ag https://www.youtube.com/watch?v=AgdMnMMbc8Q  Repair genes can be classified into pathways that use different mechanisms to reverse or bypass damage to DNA Lewin, Chapter 14