DNA Repair mechanism - Cancer Science

What is DNA Repair?

DNA repair is a fundamental process by which a cell identifies and corrects damage to the DNA molecules that encode its genome. This mechanism is vital for maintaining the integrity of genetic information over a cell’s lifespan and across generations. When DNA repair mechanisms fail, the accumulated genetic damage can lead to cancer.

How Does DNA Damage Occur?

DNA damage can occur from a variety of sources including environmental factors like ultraviolet radiation, chemical exposure, and ionizing radiation, as well as normal cellular processes like DNA replication and metabolic by-products. These damages can result in different types of lesions such as single-strand breaks, double-strand breaks, and base modifications.

Types of DNA Repair Mechanisms

There are several distinct pathways through which cells repair DNA damage:

Base Excision Repair (BER): This pathway fixes small, non-helix-distorting base lesions and involves the removal of damaged bases followed by DNA synthesis to fill the gap.
Nucleotide Excision Repair (NER): NER corrects bulky, helix-distorting lesions like thymine dimers caused by UV light.
Mismatch Repair (MMR): This mechanism fixes base mismatches and insertion-deletion loops that arise during DNA replication.
Homologous Recombination (HR): HR repairs double-strand breaks using a sister chromatid as a template for accurate repair.
Non-Homologous End Joining (NHEJ): NHEJ also repairs double-strand breaks but does not require a homologous template, making it error-prone.

How Do Defects in DNA Repair Mechanisms Lead to Cancer?

Mutations in genes responsible for DNA repair can lead to genomic instability, a hallmark of cancer. For example, mutations in the BRCA1 and BRCA2 genes, which play a role in homologous recombination, significantly increase the risk of breast and ovarian cancer. Similarly, defects in the MMR system are linked to Lynch Syndrome, a hereditary condition that elevates the risk of colorectal cancer.

How is DNA Repair Targeted in Cancer Therapy?

Given the critical role of DNA repair in maintaining genomic stability, targeting these pathways has become a strategy in cancer therapy. PARP inhibitors are a class of drugs that inhibit the enzyme poly (ADP-ribose) polymerase (PARP), which is involved in single-strand break repair. These inhibitors are particularly effective in cancers with BRCA mutations, as they exploit the concept of synthetic lethality.

What Are the Challenges in Targeting DNA Repair Mechanisms?

While targeting DNA repair mechanisms has shown promise, there are several challenges. Cancer cells can develop resistance to these therapies by upregulating alternative DNA repair pathways or through mutations that restore DNA repair capacity. Additionally, inhibiting DNA repair can also affect normal cells, leading to toxicity and side effects.

Future Directions

Research is ongoing to better understand the complexities of DNA repair and its role in cancer. This includes identifying new biomarkers for predicting response to DNA repair-targeted therapies and developing combination therapies to overcome resistance. Advances in CRISPR-Cas9 technology and next-generation sequencing are providing new insights into the genetic underpinnings of DNA repair and cancer, paving the way for more personalized and effective treatments.