Biochemical Basis of Disease Clinical Correlates Module 2

DNA Replication
Fluoroquinolones: Inhibit topoisomerases (gyrase) in E. coli; bactericidal drugs
Some anticancer drugs (camptothecin, etopside) target eukaryotic topoisomerases
Lack of telomerase in genetically engineered mice resulted in increased aging

Hutchinson-Gilford Progeria: Dramatically shortened telomeres, mutated gene for

nuclear lamins A & C

Most cancer cells have telomerase activityclinical implications unknown

DNA Repair
Hereditary non-polyposis colorectal cancer (HNPCC): Caused by deficiencies in MMR that lead
to microsatellite instability

Patients develop polyps that progress to cancer at a faster rate than the general population
does

Xeroderma Pigmentosum (XP): Mutated XP proteins (7 proteins) that make NER of pyrimidine
(T) dimers ineffective

Extreme photosensitivity, increased (2000x) rate of skin cancer, possible neurological

anomalies
NER performed by uvrABCD in prokaryotes

Cockayne Syndrome (CS): Mutations in CSA and CSB (involved in Transcription-coupled NER)

Sensitivity to sunlight, growth and developmental arrest, progressive neuro-degradation

and wasting
Cancer risk does not increase
Ataxia Telangiectasia (AT): Germline mutations in checkpoint kinase ATM (phosphorylates
proteins that trigger cell cycle arrest)
Impaired motor skills, poor balance, immunodeficiency, acute sensitivity to ionizing
radiation
Telangiecestias: Tiny, red, spider-like veins on face/eyes
20% of patients develop cancer
Nijmegen breakage syndrome: Mutation in NBS1 (part of a complex that activates ATM)
Microcephaly, growth retardation, immunodeficiency
About 50% of patients develop cancer, especially lymphomas
Blooms Syndrome: Mutations in BLM helicase lead to chromosomal instability
Severe growth retardation, characteristic facial features, butterfly-like redness on face
after sun exposure, immunodeficiency, high level of cancer risk
BRCA 1/BRCA 2: Mediate the action of RAD51 in homologous recombination

Biochemical Basis of Disease Clinical Correlates Module 2

Mutated BRCA 1/2 is responsible for 50% of familial breast cancer cases