Updated: 8/7/2018

DNA Repair

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Damage Tolerance
  • Function
    • can allow DNA replication to continue despite presence of DNA damage (e.g. thymidine dimer)
  • Process
    • DNA polymerase stalls at dimer
    • sliding clamp releases regular DNA polymerase and binds the one of two translesion polymerases
      • error free
        • recognizes that the dimer is normally a thymidine and the polymerase adds an adenosine opposite and continues replication
      • error prone
        • polymerase adds any base opposite the lesion and continues replication
Mismatch Repair
  • Process 
    • repairs G/T or A/C pairing
      • sometimes misincorporated due to tautomerization of the nucleotide
    • involves MutS, MutH, MutL enzymes
    • strand specific
      • recognizes which is the new strand because it is unmethylated and the old strand is methylated
  • Deficiency
    • hereditary nonpolyposis colorectal cancer 
      • aka Lynch syndrome
      • cause
        • hereditary absence of one copy of enzyme hMLH1 or hMSH2
          • second copy lost due to somatic mutation
            • known as the two-hit model
            • common to many DNA repair deficiencies
      • presentation
        • microsatellite instability
          • di-, tri-, tetranucleotide repeats that can be amplified
            • constant in number in normal cells
          • diagnostic in Lynch syndrome
        • ↑↑ risk of colorectal cancer
          • NOT preceded by benign polyps
Base Excision Repair
  • Function
    • specific endonucleases (glycosylases) remove bases that have been modified by several common mechanisms of damage
      • e.g. deaminated cytosines (C → U) removed by uracil glycosylase
    • can take place anytime during the cell cycle but occurs primarily in G1
  • Process
    • glycosylase specific for the damaged nucleotide removed damaged base by breaking glycosidic bond
    • damaged base removed
      • sugar remains but base removed
      • creates an apurinic/apyrimidinic (AP) site
    • gap filled by DNA polymerase
    • ligation of strand nick by DNA ligase III
Nucleotide Excision Repair
  • Function 
    • removes thymidine dimers caused by UV-B light
    • removes damaged bases caused by chemicals
  • Process 
    • maintenance repair
      • XPC recognises DNA lesion and recruits XPA
      • XPB-G binds DNA and removes a chunk spanning the damaged segment
      • DNA polymerase fills the gap
      • DNA ligase seals the nick
    • transcription-coupled repair
      • RNA polymerase stalls at DNA lesion
      • CSB and XPG recognize stalled RNA polymerase
      • CSA joins complex and removes damaged site and allows transcription to continue
  • Deficiency
    • xeroderma pigmentosum (XP)
      • cause
        • lack any enzyme XPA - XPG 
      • presentation
        • cannot repair UV damage
          • sunlight sensitivity
          • ↑↑↑ prevalence of skin cancer
          • corneal ulcers
      • diagnosis
        • measurement of repair mechanisms in white blood cells
      • treatment
        • avoidance of sunlight
    • Cockayne syndrome
      • cause
        • lack of CSA or CSB
      • AR
      • presentation
        • growth failure
        • photosensitivity
        • nervous system abnormalities
        • can affect any organ system
Homologous Recombination
  • Function
    • repair double-strand breaks
    • requires a sister chromatid to use as a template
      • therefore must occur after S phase of cell cycle
  • Process
    • double-strand break recognized by MRN complex
    • BRCA and BLM enzymes involved in end processing
    • Holliday junctions are formed
      • cross-shaped structures that mediate strand rejoining
    • junctions are resolved
      • may result in loss of heterozygosity
      • due to the use of the opposite strand as a template
  • Deficiency
    • Bloom syndrome
      • cause
        • lack of BLM helicase enzyme
      • presentation
        • short stature
        • rash from sun exposure
        • café-au-lait spot
        • leukemias, lymphomas, carcinomas
    • BRCA-1 involved in 
      • breast, prostate, and ovarian cancer
    • BRCA-2 involved in
      • breast cancer
Non-Homologous End Joining
  • Function
    • repair double-strand breaks
      • these breaks may be caused by ionizing radiation or oxidative free radicals
      • mechanism of cancer radiation therapy 
    • occurs when a sister chromatid is not available to use as a template (prior to S phase of cell cycle)
  • Process
    • break recognized by MRN complex
    • additional enzymes (Artemis, XLF, Pol μ) cut ends so they can bind
    • DNA ligase IV joins ends together
  • Deficiency
    • severe combined immunodeficiency disease (SCID)
      • one of many causes

References

 

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Questions (9)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(M1.BC.73) A 3-year-old male child is found to have a disease involving DNA repair. Specifically, he is found to have a defect in the endonucleases involved in the nucleotide excision repair of pyrimidine dimers. Which of the following is a unique late-stage complication of this child's disease? Review Topic

QID: 106551
1

Colorectal cancer

12%

(22/186)

2

Endometrial cancer

1%

(2/186)

3

Lymphomas

9%

(16/186)

4

Telangiectasia

11%

(20/186)

5

Malignant melanoma

66%

(123/186)

M1

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PREFERRED RESPONSE 5

(M1.BC.26) A 65-year-old male is treated for anal carcinoma with therapy including external beam radiation. How does radiation affect cancer cells? Review Topic

QID: 100091
1

Induces the formation of thymidine dimers

15%

(36/233)

2

Induces the formation of disulfide bonds

3%

(6/233)

3

Induces G/T and A/C pair formation

4%

(10/233)

4

Induces deamination of cytosine

5%

(11/233)

5

Induces breaks in double-stranded DNA

71%

(166/233)

M1

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PREFERRED RESPONSE 5
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(M1.BC.27) A 5-month-old male infant from a consanguineous marriage presents with severe sunburns and freckling in sun exposed areas. The mother explains that the infant experiences these sunburns every time the infant goes outside despite applying copious amounts of sunscreen. Which of the following DNA repair mechanisms is defective in this child? Review Topic

QID: 107023
1

Nucleotide excision repair

70%

(26/37)

2

Base excision repair

8%

(3/37)

3

Mismatch repair

8%

(3/37)

4

Homologous recombination

5%

(2/37)

5

Non-homologous end joining

0%

(0/37)

M1

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