Exam 3 Dna Repair

Front 1

human genome ~3x10^9 bp long

3 errors per replication per cell (1014 cells) or 1 base pair change per one billion base pairs per replication cycle

most important “proofreader” = ...

Back 1

DNA polymerase δ(delta)

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what kind of damage comes from outside sources?

Back 2

exogenous damage

Front 3

what is the damage from inside sources called?

ex. respiration

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endogenous

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for a healthy cell, rate of DNA damage = rate of ..

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repair

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what is it called when a cell is still alive and active, but no longer dividing?

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senescence

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in a diseased cell, rate of DNA damage is ... rate of repair

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greater than

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common sources of DNA damage:

-... mistakes, failure of proper proofreading during replication
-... cellular processes (oxidation, alkylation/methylation, hydrolysis)
-...(UV, X-rays, gamma irradiation)
-... (mutagens, toxins)
-heat

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spontaneous
endogenous
radiation
chemicals

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Common types of DNA damage:

mismatched bases

thymine dimers, other covalent crosslinks

...(when amine group is removed)

..., ... (base is absent)

single-stranded and double-stranded breaks

bulky adduct formation

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deamination
apurination
apyrimidination

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DNA repair: nucleases hydrolyze ... bonds

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phosphodiester bonds

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... --> remove single nucleotides from either the 5’ or 3’ end of a nucleic acid
-recall that ... exhibits 3’--> 5’ exonuclease activity

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exonucleases
DNA polymerase

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... --> cut within the DNA and release nucleic acid fragments
-...: corrects “AP” sites (apurination or apyrimidination)

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endonucleases
AP endonuclease

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Common steps in DNA repair mechanisms involves:

DNA polymerase or ... removes mistake

... replaces mistake with proper bases

... rejoins repaired segments

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AP endonuclease
DNA polymerase
DNA ligase

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When you need to replace a single base, you use ... or ...

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base excision repair
mismatch repair

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when you want to replace multiple bases due to extensive damage, you use ... repair

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nucleotide excision

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Base excision repair:

chemical alteration of a ... base (oxidation, deamination, alkylation)

-problem is ... bases

involves specific DNA ...(recognizes and removes modified base) and ...

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single
cytosine
glycosylase
AP endonuclease

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An example of base excision repair: Cytosine Deamination

-uracil can arise in DNA through spontaneous deamination of cytosine

-U pairs with A in DNA, forming U-A base pair (instead of normal C-G pair that would have formed prior to the deamination)

-need ... to recognize and remove, leaving an ... (a hole) that is filled in with DNA polymerase

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uracil glycosylase
abasic site

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nucleotide excision repair:

multisubunit enzyme complex recognizes a ... created by chemical alteration or through UV-induced damage
-... (from UV)
-benzo[a]pyrene adducts on ... (from cigarette smoke)

-involves ... and ... (unwinds DNA) activity within the enzyme complex

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bulky lesion
thymine dimers
guanine
endonuclease
helicase

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Mismatch repair

recognizes and replaces erroneous ..., ..., mis-incorporations, and damage (ex: G/T or A/C base pair)

prevents uncontrolled proliferation of cells

involves ...
-tumor suppressor genes
-mutated in some forms of cancer (like HNPCC)
-3 types

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insertions
deletions

Mut proteins

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methyl groups (CH3) act as ... to tell the enzymes that it's the parent strand

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signals

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DNA repair diseases:

most involve genetic defects in ... repair or ... repair

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nucleotide excision
mismatch

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which disease is this?

basic defect is in nucleotide excision repair (ex: pyrimidine/thymine dimers), leading to deficient repair of DNA damaged by UV radiation

photosensitivity, pigmentary changes, premature skin aging, and malignant melanoma and squamous cell carcinoma

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Xeroderma Pigmentosum (XP)

Front 22

which disease is this?

abnormal sensitivity ionizing radiation (especially x-rays), which leads to chromosomal breaks

... mutated (ATM) protein involved in cell cycle control and DNA repair
-encodes a kinase that is essential for p53 activity
-p53 prevents a cell with damaged DNA from entering the S phase

may be linked to accelerated telomere loss (accelerates aging process)

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ataxia-telangiectasia (A-T)
ataxia-telangiectasia

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... is a tumor suppressor

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p53

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Ataxia Telangiectasia

-lack of ... coordination (ataxia)
-oculo-cutaneous telangiectasia (small red spider veins)
-cerebellar dysfunction
-recurrent sino-pulmonary infections (caused by immunodeficiency)
-predisposition to ...(particularly lymphomas and leukemias)
-most become wheelchair bound by the age of 10

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muscle
cancer

Front 25

which disease is this?

mutation in DNA excision repair

hypersensitivity to UV light

unlike other DNA repair diseases, not linked to cancer

average lifespan is 12 years

Symptoms: growth deficiency (dwarfism), premature aging, demyelination, impaired development of the nervous system, thin skin and hair, sunken eyes, stooped posture, pigmentary retinal degeneration, photosensitivity

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Cockayne Syndrome

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which disease is this?

genetic defects in genes involved in DNA replication mistakes (mismatch repair)

increased risk of cancers of the colon, rectum, stomach, small intestines, liver, gallbladder ducts, upper urinary tract, brain, skin, endometrium, ovary, and prostate

may have noncancerous colon polyps at an earlier age

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HNPCC (hereditary nonpolyposis colorectal cancer, or Lynch Syndrome)

Front 27

which disease is this?

mutation in DNA helicase and abnormalities in excision repair of UV-damaged DNA

brittle and fragile hair, congenital ichthyosis, progeria-like face, mental retardation, premature aging

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Trichothiodystrophy (TTD)