DNA Damage, Aging and cancer Jan H.J. Hoeijmakers, Ph.D.

Nermeen Jouda 430203995

Bch 550

Supervised by Dr Gihan

Sources of DNA damage

Figure 1. Sources and Consequences of DNA Damage.

DNA integrity is threatened from three sides

First, spontaneous reactions (mostly hydrolysis)example: deamination.

Second, our own metabolism generates reactive oxygen and nitrogen species, all of which damage DNA.

Third, DNA is damaged by exogenous physical and chemical agents.

DNA Lesions That Require RepairDNA Lesion Example/Cause

Missing baseRemoval of purines by acid and heat (under physiological conditions ≈104 purines/day/cell in a mammalian genome); removal of altered bases (e.g., uracil) by DNA glycosylases

Altered base Ionizing radiation; alkylating agents (e.g., ethylmethane sulfonate)

Incorrect base Mutations affecting 3′ → 5′ exonuclease proofreading of incorrectly incorporated bases

Bulge due to deletion or insertion of a nucleotide

Intercalating agents (e.g., acridines) that cause addition or loss of a nucleotide during recombination or replication

Linked pyrimidines Cyclotubyl dimers (usually thymine dimers) resulting from UV irradiation

Single- or double-strand breaks

Breakage of phosphodiester bonds by ionizing radiation or chemical agents (e.g., bleomycin)

Cross-linked strands Covalent linkage of two strands by bifunctional alkylating agents (e.g., mitomycin C)

3′-deoxyribose fragments

Disruption of deoxyribose structure by free radicals leading to strand breaks

Nucleotide-excision repair Nucleotide-excision repair eliminates helix-

distorting lesions — such as those caused by Uv induced photoproducts — in a multistep, “cut and- patch” reaction that involves more than 30 proteins .It has two branches:

global genome repair, which probes the genome for strand distortions

transcription-coupled repair, which removes distorting lesions that block elongating RNA polymerases

Diseases of Nucleotide-Excision Repair

Xeroderma Pigmentosum Hypersensitivity to the sun skin cancer. defects in global repair,

with or without deficiencies in transcription- coupled repair of distorting lesions.

accelerated neurodegeneration

Defects in the repair-enzyme genes XPA through XPG.

Cockayne’s Syndrome UV sensitive . Growth failure. No skin cancer. Impaired sexual development severe and progressive neuro-

dysfunction Mutations in transcription-coupled repair in the gene

encoding CSA or CSB combind with XPB, XPD and XPG

Trichothiodystrophy ( TTD)

UV sensetive Similar to Cockayne’s

Syndrome in addition to brittle (unfinished)

hair and nails Point mutations in the genes

encoding XPB and XPD

Excision repair in cancer and aging.

UV lesions and helix-distorting chemical adducts are recognized and repaired by a multi-protein nucleotide excision repair (NER) complex comprising two pathways:

global genome (GG) NER and transcription-coupled excision repair (TCR).

Patients who have a defective GG-NER pathway are highly susceptible to skin cancer, whereas defects in TCR lead to progeroid syndromes.

Summary DNA damage can trigger the development

of cancer, accelerate aging, or both, depending on the type, amount, and location of the damage.

When the damage is not repaired, the outcome may be cancer or, if cell death or senescence occurs, protection from cancer, but the trade-off is acceleration of the aging process.