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Announcements. http://cwx.prenhall.com/bookbind/pubbooks/klug3/ Self-grading problems = good practice for exam. Review of Last Lecture. 1. Post-transcriptional gene regulation: Alternative splicing 2. Classification of mutations 3. Detection of mutations in humans

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slide1

Announcements

  • http://cwx.prenhall.com/bookbind/pubbooks/klug3/

Self-grading problems = good practice for exam

slide2

Review of Last Lecture

1. Post-transcriptional gene regulation: Alternative splicing

2. Classification of mutations

3. Detection of mutations in humans

4. Different forms of mutations

slide3

Outline of Lecture 29

I. Origins of mutation

II. Mechanisms of DNA repair

III. Transposable elements

slide4

I. Different origins of mutation

1. Tautomeric Shifts: spontaneous

2. Base Analogues: chemical

3. Alkylating Agents: chemical

4. Intercalating Dyes: chemical

5. Deamination: chemical

6. UV Radiation and Thymine Dimers

7. High-Energy Radiation (X rays, gamma rays, cosmic rays)

environmental

slide6

Formation of a TA to CG Transition During DNA Replication

Transition is a purine replaced by different purine or pyrimidine

replaced by different pyrimidine.

slide7

2. Base Analogues: DNA can

Incorporate 5-BU in place of Thymine

rare

common

Changes T-A pair > C-G pair. T > C, and A > G are both Transitions

slide8

3. Alkylating Agents: Ethylmethane

Sulfonate (EMS) Alkylates Guanine

Note: changes a G-C pair into an A-T pair

(G > A is a transition, C > T is a transition)

Another example: mustard gases first used in WWII.

slide9

4. Intercalating Dyes Cause Frameshifts

Intercalate themselves into the DNA double helix, distorting it,

and causing insertion or deletion during DNA replication or

recombination. Other examples: Ethidium Bromide, DAPI.

slide10

5. Deamination is Caused by Nitrous Acid

(a) Causes: C -> U/T transition (and G -> A transition)

Causes: A -> G transition (and T -> C transition).

Deamination can be spontaneous as well.

slide11

6. Ultraviolet Radiation Cause

Thymine Dimers

Disrupts synthesis;

good for sterilization

of bacteria, bad for skin cancer.

260 nanometer

wavelength

slide13

Effects of Ionizing Radiation

  • Causes either point mutations or breaks in phosphodiester bonds of DNA backbone.
  • If both strands broken, there can sometimes be repair in mammals through the double-strand break repair (DSB) system.
  • Dividing cells are more susceptible to therapeutic X-rays than non-dividing cells (radiation therapy for cancer).
slide14

Example of ionizing radiation

1986 - nuclear reactor in Chernobyl, Soviet Union overheated, exploded, and ejected radioactive material into the environment - largest radiation accident in world.

Gamma rays emitted from radioactive elements are a source of ionizing radiation: 31 killed, 200 + acute radiation sickness, longterm effects ???

No increase so far in # of leukemias, but significant increase in # of childhood thyroid cancers

normal - 0.5-3 cases / million children

now- 100 cases / million children

slide15

Ionizing radiation transforms stable atoms into reactive free radicals and ions, which cause mutations in DNA

slide16

Radiation Doses in Perspective

Category Dose (mSv, millisievert)

Lethal full-body dose 3000

Detectable increase in cancer > 200

Chernobyl cleanup worker 250

Chernobyl nearby resident 50

Germany resident 0.4-0.9

Average yearly medical 0.39

Yearly background 2-3

Yearly smoking 2.8

slide17

Irradiation of Food (and Mail?)

  • Food/mail is exposed to X rays or electrons; doesn’t contact radioactive material or become radioactive itself.
  • Pro:
    • Prevents spoilage of food.
    • Reduces bacterial food-borne diseases.
    • Reduces reliance on chemical preservatives.
  • Con:
    • Produces chemical changes in food (so do other preservation methods); safe?
    • Selects for radiation-resistant bacteria?
slide18

II. Mechanisms of DNA Repair

  • Prokaryotic:
    • Photoactivation Repair
    • Base Excision Repair
    • Post-replication Repair and SOS Repair
  • Eukaryotic:
    • Nucleotide Excision Repair
    • Proofreading and Mismatch Repair
    • Double-Strand Break Repair
slide19

Photoactivation Repair in Prokaryotes

UV

Photoreactivation

Enzyme Cleaves

bond between T’s

Visible light

slide20

Base Excision Repair in Prokaryotes

DNA glycosylase

Apyrimidinic endonuclease

DNA Pol I, DNA ligase

slide22

Model for Eukaryotic Nucleotide Excision Repair: Xeroderma Pigmentosum

Mottled redness and

pigmentation sign of

damage due to UV

exposure. Precursor

to cancer. 4 years old.

Carefully protected from

sunlight. 18 years old.

Works as a model.

7 Complementation Groups deficient in Excision Repair identified by Cell-cell Hybridization.

slide23

Proofreading and Mismatch Repair

  • Most DNA polymerases contain “proofreading” activity (3’ to 5’ exonuclease); increases fidelity of replication by 100X.
  • Remaining errors fixed by Mismatch Repair:
    • How does system recognize which strand is correct for use as template?
    • In bacteria, old strands become methylated, repair system recognizes unmethylated new strands. Similar system may work in eukaryotes.
slide25

Double-Strand Break Repair in Eukaryotes

  • When both strands are broken and template can’t be used to repair the damage, DSB repair pathway reanneals two DNA segments.
    • Homologous recombination repair uses DNA from undamaged homologue (!)
    • Nonhomologous recombination repair also occurs.
  • Defects in this pathway associated with X-ray hypersensitivity and immune deficiency.
slide26

Site-directed mutagenesis

Using mutations to study gene function in the lab

Change 1 or more nucleotides in a gene to change a triplet codon and thus the amino acid sequence of the protein

Introduce mutated gene into animal

Determine effect on gene expression and protein function

slide28

III. Transposable Elements

  • Also called Transposons or “Jumping Genes”; can move within the genome.
  • Present in all organisms; well-studied in bacteria, maize, flies.
  • Discovered in Maize Ac-Ds system:
slide32

P elements in Drosophila

  • P elements are transposons in flies.
  • The can be used experimentally create mutants, mark the positions of genes, or clone genes.
  • They can also be used to insert genes into the genome, creating a transgenic fly.
slide33

Transposons in Humans

  • Alu family of short interspersed elements (SINEs)
    • Moderately repetitive DNA
    • 500,000 copies of 200-300 bp repeats
  • Medical example: a transposon jumped into the gene on X chromosome responsible for hemophilia
    • Not present on either X chromosome of mother
    • Present on chromosome 22 of mother