**1. Introduction**

530 Selected Topics in DNA Repair

[77] Marston NJ, Richards WJ, Hughes D, Bertwistle D, Marshall CJ, Ashworth A.

[78] Murakawa Y, Sonoda E, Barber LJ, et al. Inhibitors of the proteasome suppress

[79] da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. *Annu* 

[80] Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human

[81] TCGA. Comprehensive genomic characterization defines human glioblastoma genes

[82] Dittmann K, Mayer C, Fehrenbacher B, et al. Radiation-induced epidermal growth

[83] Liccardi G, Hartley JA, Hochhauser D. EGFR nuclear translocation modulates DNA

[84] Mukherjee B, McEllin B, Camacho CV, et al. EGFRvIII and DNA double-strand break

[85] Li L, Wang H, Yang ES, Arteaga CL, Xia F. Erlotinib attenuates homologous

[86] Golding SE, Rosenberg E, Neill S, Dent P, Povirk LF, Valerie K. Extracellular signal-

[87] Burkitt K, Ljungman M. Phenylbutyrate interferes with the Fanconi anemia and BRCA

[88] Koll TT, Feis SS, Wright MH, et al. HSP90 inhibitor, DMAG, synergizes with radiation

[89] Camphausen K, Tofilon PJ. Inhibition of Hsp90: a multitarget approach to radiosensitization. *Clin Cancer Res.* Aug 1 2007;13(15 Pt 1):4326-4330. [90] Dote H, Burgan WE, Camphausen K, Tofilon PJ. Inhibition of hsp90 compromises the DNA damage response to radiation. *Cancer Res.* Sep 15 2006;66(18):9211-9220. [91] Johnson N, Cai D, Kennedy RD, et al. Cdk1 participates in BRCA1-dependent S phase

factor receptor nuclear import is linked to activation of DNA-dependent protein

repair following cisplatin and ionizing radiation treatment. *Cancer Res.* Feb 1

repair: a molecular mechanism for radioresistance in glioblastoma. *Cancer Res.* May

recombinational repair of chromosomal breaks in human breast cancer cells. *Cancer* 

related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response. *Cancer Res.* Feb 1

pathway and sensitizes head and neck cancer cells to cisplatin. *Mol Cancer.* 

of lung cancer cells by interfering with base excision and ATM-mediated DNA

checkpoint control in response to DNA damage. Mol Cell. Aug 14 2009;35(3):327-

glioblastoma multiforme. *Science.* Sep 26 2008;321(5897):1807-1812.

and core pathways. *Nature.* Oct 23 2008;455(7216):1061-1068.

kinase. *J Biol Chem.* Sep 2 2005;280(35):31182-31189.

1999;19(7):4633-4642.

2007;67(18):8536-8543.

2011;71(3):1103-1114.

2007;67(3):1046-1053.

2008;7:24.

339.

15 2009;69(10):4252-4259.

*Res.* Nov 15 2008;68(22):9141-9146.

repair. *Mol Cancer Ther.* Jul 2008;7(7):1985-1992.

*Rev Pathol.* Feb 28 2011;6:49-69.

Interaction between the product of the breast cancer susceptibility gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals. *Mol Cell Biol.* Jul

homologous DNA recombination in mammalian cells. *Cancer Res.* Sep 15

Our skin is equipped with specialized cells and mechanisms that defend our bodies against pathogens, heat, and water loss. Today, our skin is exposed to increased environmental stress including solar ultraviolet radiation (which results in direct and indirect DNA damage) and atmospheric pollutants. Ozone depletion from the earth's atmosphere as well as expanding industrial processes has led to increased exposure to pollutants including pesticides and cigarette smoke. While UV radiation, and in particular its UV-B component (280-315 nm), has several health benefits (including production of vitamin D3) (Reichrath, 2008) continuous exposure is the primary source of UV-induced DNA damage.

The sun produces UV radiation classified into three broad bands. The highest energy UV-C (100-280 nm) radiation is largely absorbed by the earth's atmosphere and thus does not affect humans. Meanwhile, the UV-B component is partially absorbed by the atmosphere and UV-A (315-400 nm) is primarily unabsorbed. While lower energy UV-A radiation penetrates beyond the epidermis, higher energy UV-B radiation primarily affects the outermost epidermal layer of skin.

Harm to the body's barrier can lead to DNA mutation or DNA replication inhibition in the skin and eyes (cataracts) and may lead to broader immunosuppression (Britt, 1995). The most serious skin cancer (malignant melanoma) occurs when excitation of a chromophore leads to either direct reaction of the excited molecule with DNA or in the production of a free radical which may also react with DNA. Since the body produces oxygen free radicals (ROS) as part of normal metabolism (during ATP production), it is able to combat oxidative stress through endogenous antioxidants.

The body's protective system, however, may become overwhelmed and compromised by environmental factors, age, or disease. Aging leads not only to increased total exposure but also to a decrease in production of endogenous antioxidants (enzymes and vitamins) and an increased risk of DNA damage. Oxidative stress can also lead to damage to other cellular components including lipids and proteins. A naturally-derived method to enhance protection against environmental factors that eventually overwhelm the body's defense mechanisms is discussed. Another major risk of UV radiation is oxidative damage to lipids (peroxidation) and proteins. Cell membranes, which are composed of lipids, are especially

The Botanical Extract Feverfew PFE Reduces

**4. DNA repair mechanism in plants** 

these findings in a clinical setting.

variety of areas.

DNA damage.

et al., 2004).

pathways.

DNA Damage and Induces DNA Repair Processes 533

antioxidants. Because several types of ROS may be formed through environmental insult, several types of antioxidants are produced in the skin. Thus antioxidants come in various forms (vitamins, enzymes, etc.) and may be either lipophilic or hydrophilic to function in a

In plants, UV radiation-induced DNA damage can lead to DNA replication inhibition. Although plants exhibit mechanisms by which they are able tolerate some DNA damage, DNA mutation can still lead to transcription and replication blocks. Since plants, like humans, are subjected to oxidative stress (including that induced by UV radiation), an investigation into the evolutionary response by plants to this stress may allow us to apply

By their nature, plants are subjected to solar UV radiation indiscriminately. They must necessarily, then, possess inherent methods to prevent and repair DNA damage. While plants are better able to absorb the high energy UV radiation through various photonabsorbing structures, they are still at high risk for oxidative modification of DNA. DNA repair mechanisms in plants such as Arabidopsis thaliana have been investigated and serve as a foundation for the search of a botanical extract that can effectively combat UV-induced

Repair mechanisms increase the likelihood of the accurate transmission of genetic information from parent to daughter cell and thus the survival of the species. Although plants have developed methods to minimize the toxic effects of DNA damage including DNA translesion synthesis and recombination (Schmitz-Hoerner and Weissenbock, 2003), they also have active repair pathways. These pathways include photoreactivation (via photolyase), nucleotide excision repair, base excision repair, and mismatch repair (Kimura

Plants and some other organisms are able to use light energy (UV and visible) to reverse DNA damage. The enzyme photolyase binds to CPDs and via photoreactivation removes UV-induced lesions. Additionally, excision repair pathways work by replacing damaged DNA with new nucleotides. Base excision repair (BER) employs various DNA glycosylases to remove modified DNA. On the other hand, nucleotide excision repair (NER) is essential in solar radiation protection and in repairing a wide range of DNA lesions. A complex array of proteins recognize, bind to, excise, and repair DNA irregularities in both excision repair

Humans share repair pathways with plants, particularly nucleotide excision repair (NER). NER is essential in removing major damage to DNA which interferes with the genetic code. Due to similarities in DNA damage and repair mechanisms in plants and humans,

Feverfew (*Tanacetum parthenium*) is a plant that has been used as a medicinal herb for centuries throughout Eastern Europe and more recently North America. Traditionally, it was used for its anti-inflammatory properties to treat migraine headaches, fever, and arthritis. Additionally, feverfew has shown to exhibit powerful antioxidant activity. Although feverfew leaves contain skin irritating compounds called parthenolides,

metabolites produced by plants may provide beneficial effects in humans.

**5. Botanical extracts | Feverfew PFE as an antioxidant** 

prone to the damaging effect of free radicals (Sen, et al., 2010). Prolonged oxidative stress to the lipid bilayer can lead to membrane rupture and apoptosis. Lipid peroxidation is, in fact, used as a marker of oxidative stress since the lipid membrane is easily attacked by free radicals.

Cellular DNA damage caused by UV radiation may be classified into two components. The first is that caused by an immediate photochemical reaction (direct) while the other is caused by the formation of ROS (indirect). Direct damage (through direct UV absorption) results primarily in the DNA product cyclobutane-pyrimidine dimer (CPD) (Farage, et al., 2010). On the other hand, indirect damage (through ROS formation) causes DNA mutation due to a replication error induced by modified guanine base (8-oxo-guanine). Direct UV absorption also leads to the formation of 8-oxo-guanine (8oGua) as well as the photoproduct pyrimidine (6-4) pyrimidinone although in proportionally lower amounts.
