Ch. 35: DNA Damage and Repair

mutation

permanent changes in the DNA, lead to evolution and diversity in species

hereditary mutations

passed from parent to child

de novo mutations

spontaneous in a fertilized egg

somatic mutations

in individual cells, not passed to offsprings

genetic variant

mutation that is not in a gene or regulatory region, or is in a neutral gene (not selected for or against and randomly passed on)

mutations arise by

either spontaneous errors in replication or a mutagen

spontaneous errors

mis-match (incorrect base), insertion or deletion

mutagens

interacts with DNA, causing a structural change that affects base-pairing capability of altered nucleotide or damages the DNA

mismatch/substitution

most common source of mutation, when the wrong bases are paired together, most are fixed by DNA pol. III

mutagen

any agent that alters DNA after replication is complete

oxidizing agents

reactive oxygen species from radiation, air pollution, chemicals and oxidizes guanine usually (8-oxoguanine which then mispairs with adenine)

deaminating agents

causes deamination of cytosine to uracil

alkylating agents

cause mismatch and prevent replication by alkyl groups attacking DNA, some bifunctional agents can cause intrastrand linking and cross-linking on DNA, preventing replication

pyrimidine dimers

occur with exposure to UV light, when double bond in pyrimidine is opened and bonds adjacently with another pyrimidine to form a tight ring, double helix is distorted causing replication to fail

ionizing radiation

from environment, necessary medical tests, or man-made, breaks the sugar/phosphate backbone, breaks hydrogen bonds between bases, or damages bases

overall mechanism for DNA repair

use sequence from the uncompromised strand, recognize incorrect base, remove it, DNA polymerase adds correct nucleotide, DNA ligase seals nick

direct repair

enzymes act directly on bases to remove bulky adducts and do not break the backbone

mismatch repair

corrects errors that cannot be fixed by proofreading, exonuclease cuts free end of DNA, endonuclease cuts middle of DNA

base-excision repair

DNA glycolysis hydrolyzes glycosidic bond, AP endonuclease nicks sugar phosphate backbone, deoxyribose phosphodiesterase excises deoxyribose phosphate, DNA pol. I fills gap, DNA ligase seals strands together

nucleotide-excision repair

removes UV induced damage, excinuclease removed mutated (12-15 bases) fragment, DNA pol. I synthesizes new, DNA ligase joins trands

excinuclease

excision repair endonuclease

recombination

homology directed repair, exchange of genetic information between 2 DNA molecules to repair DNA breaks, involves many enzymes

non-homologous end joining (NHEJ)

broken ends are directly ligated back together with no template, occurs rapidly and not subject to any stage of cell cycle, most frequent but error prone mechanism of repair