DNA Damage & Repair and its Therapeutic Potential

Since DNA was first discovered by researchers, decades of work have been done to understand its importance as it is the code of life itself. While DNA is the cornerstone of life, it is not immune to damages, and as so it is vital for DNA to repair itself for normal cell function to be maintained. Though, DNA is not always able to repair itself and this leads to some diseases such as various cancers. Fortunately, DNA repair pathways are capable of being tools to provide therapies to combat these diseases.

Introduction to DNA Damage and Repair

Over the course of one day within the human body, there are thousands of instances of DNA damage that are the result of both endogenous and exogenous factors. Some examples of exogenous reasons for DNA damage are ultraviolet (UV) radiation from the sun and the chemicals from tobacco in cigarette smoke. On the other hand, endogenous DNA damage can occur from metabolic processes within the body. For example, one metabolic process can produce reactive oxygen which can damage DNA.

When enough DNA is damaged, apoptosis, a form of programmed cell death, can occur. Though, when there is no apoptotic control, DNA damage may result in cancer. An example of this is skin cancer which is caused by overexposure to UV rays from the sun, tanning beds, or sunlamps. In the short term, this damage can cause a sunburn but, over time, UV damage adds up. This leads to changes in skin texture, premature skin aging, and even skin cancer.

For these reasons, it is necessary to have a repair system for DNA. For as often as DNA damage is happening throughout the body, so is DNA repair. Some repair pathways repair double stranded DNA breaks, which is when both strands of the DNA have damage at the same location. Other repair pathways repair single stranded breaks, where only one DNA strand has missing or incorrect nucleotide(s).

Types of DNA Repair

Double stranded break repair:

1. HR: Homologous repair
   • In HR, the homologous chromosome is used as a template to fix the damage. This pathway features the BRCA family.
2. NHEJ: Non-homologous end joining
   • In NHEJ, the broken DNA strands are reconnected without any attempt to replace what was previously there.

Single stranded break repair:

1. BER: base excision repair
   • In BER, the single stranded DNA break is fixed using the complementary DNA strand as a template. This pathway features the PARP family.
2. NER: Nucleotide excision repair
   • The NER pathway also repairs single stranded DNA breaks by using the complementary DNA, however it repairs damage caused by ultraviolet light.
3. MMR: DNA mismatch repair
   • MMR fixes incorrect nucleotide pairings in the DNA.

Cancer Treatment Using DNA Repair Pathways: PARP Inhibitors

BRCA1 and BRCA2 are important in homologous repair, and when they are mutated, cells can become cancerous. While the rate of breast cancer for women without BRCA1 or 2 mutations is 13%, a BRCA1 or 2 mutation increases the likelihood of developing breast cancer up to 45-72%.

When a cell loses its ability to undergo homologous repair and becomes cancerous, base excision repair (BER) becomes its primary method of DNA repair. Although there are other repair pathways, they are less reliable and more error prone. Therefore, if the BER pathway is inhibited, the BRCA-deficient cancer cell will not have a reliable repair system, and it will accumulate DNA damage that will trigger cell death.

One way to inhibit the BER pathway is through targeting a protein called PARP (poly-ADP ribose polymerase) which plays a vital role in BER. This can be done using a PARP inhibitor, which binds to PARP when it is on DNA to stop it from performing its function. PARP inhibitors are small molecules, and there are several currently on the market, such as olaparib, rucaparib, and talazoparib. The inhibition of PARP when it is bound to DNA will not only prevent single stranded DNA breaks from being fixed, but, it also causes PARP to be trapped on the DNA. Then, if the cell tries to replicate its DNA, the trapped PARP protein will be in the way, and a double stranded break will occur. This will drastically speed up the occurrence of DNA damage, and apoptosis of the cancer cell will occur. There are many other potential targets to utilize DNA repair pathways as cancer therapies.

Conclusion

Since DNA damage occurs constantly, it is vital for our cells to have a reliable DNA repair response. However, there are times when blocking a form of DNA repair is beneficial, such as when targeting certain types of cancer cells.

ABclonal offers a variety of antibodies, proteins, and ELISA kits covering DNA damage and repair. We have currently over 150 related antibodies with multiple applications in our inventory. ABclonal is committed to continued development of additional products involved in DNA damage and repair to meet the growing market demand.

Available Antibodies for DNA Damage and Repair Research

References

Bernstein, C., Prasad, A.R., Nfonsam, V., and Bernstein, H. (May 22nd 2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Clark Chen, IntechOpen, DOI: 10.5772/53919. Available from: https://www.intechopen.com/chapters/43929.

BRCA gene Mutations: Cancer risk and genetic testing fact sheet. National Cancer Institute. (2020). https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet#r2.

Herceg, Z., and Wang, Z.-Q. (2001). Functions of poly(adp-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 477(1-2), 97–110. https://doi.org/10.1016/s0027-5107(01)00111-7.

Hoeijmakers, J. H. J. (2009). DNA Damage, Aging, and Cancer. The New England Journal of Medicine, 316(15). https://doi.org/10.1056/nejmra0804615.

Konecny, G. E., and Kristeleit, R. S. (2016). PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: Current practice and future directions. British Journal of Cancer, 115(10), 1157–1173. https://doi.org/10.1038/bjc.2016.311.

Kunkel, T. A., & Erie, D. A. (2005). DNA mismatch repair. Annual Review of Biochemistry, 74(1), 681–710. https://doi.org/10.1146/annurev.biochem.74.082803.133243

McCabe, N., Turner, N. C., Lord, C. J., Kluzek, K., Białkowska, A., Swift, S., Giavara, S., O'Connor, M. J., Tutt, A. N., Zdzienicka, M. Z., Smith, G. C. M., & Ashworth, A. (2006). Deficiency in the repair of dna damage by homologous recombination and sensitivity to poly(adp-ribose) polymerase inhibition. Cancer Research, 66(16), 8109–8115. https://doi.org/10.1158/0008-5472.can-06-0140.