1. Describe the process of DNA repair and its significance in maintaining genomic stability.
Answer: DNA repair is a critical mechanism by which cells fix errors or damage to their DNA, ensuring that the genetic material remains intact and functional. Various repair mechanisms include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double-strand break repair mechanisms like homologous recombination (HR) and non-homologous end joining (NHEJ). DNA repair is essential for preventing mutations that can lead to genomic instability, which is a key driver in the development of cancer. When DNA repair mechanisms fail or are overwhelmed, it increases the likelihood of cancer-causing mutations.
2. How do mutations in DNA repair genes contribute to cancer development?
Answer: Mutations in DNA repair genes can impair the repair of DNA damage, allowing mutations to accumulate in the genome. These mutations may affect tumor suppressor genes, oncogenes, or other critical genes involved in cell cycle regulation. For example, mutations in the BRCA1 and BRCA2 genes compromise DNA repair, increasing the risk of breast and ovarian cancer. Defects in mismatch repair genes, such as MLH1 and MSH2, are associated with Lynch syndrome and colorectal cancer. When the repair system is faulty, it accelerates the accumulation of mutations that drive cancer progression.
3. What is the role of p53 in the DNA damage response and cancer prevention?
Answer: p53 is a tumor suppressor protein that plays a pivotal role in the DNA damage response. Upon detecting DNA damage, p53 activates cell cycle arrest, allowing time for repair mechanisms to fix the damage. If the damage is irreparable, p53 can initiate apoptosis (programmed cell death) to prevent the proliferation of cells with faulty DNA. Mutations in the p53 gene are commonly found in many cancers, leading to the inability to repair DNA properly or induce cell death, thus increasing the risk of cancer.
4. How does homologous recombination repair contribute to preventing cancer?
Answer: Homologous recombination (HR) is a precise DNA repair mechanism that fixes double-strand breaks (DSBs), often caused by radiation or oxidative stress. HR uses an undamaged sister chromatid as a template to accurately repair the break. This process is crucial for maintaining genomic stability. Defects in HR, as seen in mutations in BRCA1 and BRCA2, result in an inability to repair DSBs efficiently, leading to chromosomal instability and an increased risk of cancers such as breast, ovarian, and prostate cancer.
5. Explain the role of base excision repair (BER) in preventing mutations that lead to cancer.
Answer: Base excision repair (BER) is responsible for repairing small, non-helix-distorting base lesions, such as those caused by oxidative damage, alkylation, or deamination. The BER pathway involves the removal of damaged bases by DNA glycosylases, followed by the excision of the sugar-phosphate backbone and synthesis of a new, correct base. BER is crucial for preventing mutations that can occur from oxidative stress and environmental carcinogens. Failure of BER can lead to mutations that accumulate over time and increase the likelihood of cancer development.
6. What are the consequences of defective nucleotide excision repair (NER) in cancer prevention?
Answer: Nucleotide excision repair (NER) is responsible for repairing bulky, helix-distorting DNA lesions, such as those caused by ultraviolet (UV) light or chemical mutagens. NER removes a section of the damaged DNA strand and fills the gap with newly synthesized DNA. Defective NER, as seen in conditions like xeroderma pigmentosum, leads to an increased sensitivity to UV radiation and a significantly higher risk of skin cancers. These individuals have a reduced ability to repair UV-induced DNA damage, which results in an accumulation of mutations and cancer risk.
7. How does the mismatch repair (MMR) system contribute to cancer prevention?
Answer: Mismatch repair (MMR) is a DNA repair mechanism that corrects errors made during DNA replication, such as base-base mismatches or small insertions and deletions. MMR proteins, including MLH1, MSH2, MSH6, and PMS2, recognize mismatched base pairs, excise the incorrect DNA segment, and replace it with the correct sequence. Defective MMR is associated with Lynch syndrome, an inherited cancer syndrome that predisposes individuals to various cancers, including colorectal cancer. When MMR is compromised, errors accumulate in the genome, leading to microsatellite instability and increased cancer risk.
8. What is the connection between DNA repair and genomic instability in cancer cells?
Answer: Genomic instability is a hallmark of cancer cells and arises when DNA repair mechanisms fail to fix DNA damage properly. This leads to the accumulation of mutations, chromosomal rearrangements, and aneuploidy (abnormal number of chromosomes), all of which contribute to cancer progression. DNA repair deficiencies, such as in HR, BER, or NER, result in the inability to correct mutations and repair double-strand breaks, promoting genomic instability. The continuous cycle of DNA damage and repair failure enables the selection of cells with mutations that drive tumorigenesis.
9. Discuss the role of non-homologous end joining (NHEJ) in preventing cancer.
Answer: Non-homologous end joining (NHEJ) is a repair pathway that fixes double-strand breaks (DSBs) by directly ligating the broken ends together, without the need for a homologous template. While NHEJ is error-prone and can lead to small insertions or deletions at the break site, it is essential for repairing DSBs in cells that are not actively dividing and do not have a sister chromatid available for homologous recombination. Impairment in NHEJ can lead to chromosomal instability, which increases the risk of cancer. However, excessive reliance on NHEJ may also promote oncogenic mutations.
10. How does oxidative stress contribute to DNA damage and cancer risk?
Answer: Oxidative stress occurs when there is an imbalance between reactive oxygen species (ROS) and the body’s ability to neutralize them with antioxidants. ROS can cause a wide variety of DNA lesions, including base modifications, strand breaks, and cross-links. If not repaired, these oxidative damages can lead to mutations, chromosomal fragmentation, and genomic instability. Over time, the accumulation of such mutations can promote cancer development. Efficient DNA repair mechanisms, such as base excision repair (BER), are essential to counteracting oxidative damage and reducing cancer risk.
11. What are the main types of DNA damage caused by UV radiation, and how do repair mechanisms counteract these damages?
Answer: UV radiation primarily causes thymine dimers, which are covalent bonds formed between adjacent thymine bases in the DNA. This distorts the DNA helix and can block replication and transcription. Nucleotide excision repair (NER) is the primary repair mechanism for fixing UV-induced damage. NER recognizes and excises the damaged segment of the DNA strand, replacing it with a correctly synthesized sequence. Defects in NER, such as those found in xeroderma pigmentosum, result in an inability to repair UV-induced damage, increasing the risk of skin cancers.
12. How does the Fanconi anemia pathway contribute to DNA repair and prevent cancer?
Answer: The Fanconi anemia (FA) pathway is involved in the repair of DNA interstrand crosslinks, which prevent DNA replication. When these crosslinks occur, the FA pathway recognizes the damage, assembles a protein complex that promotes the repair of the crosslinks, and ensures proper DNA replication. Defects in the FA pathway, as seen in Fanconi anemia syndrome, result in the accumulation of crosslinks and mutations, leading to a higher risk of developing cancers, especially leukemia and solid tumors.
13. How does the DNA damage checkpoint contribute to cancer prevention?
Answer: DNA damage checkpoints are critical surveillance mechanisms that detect DNA damage and halt the cell cycle to allow for repair. Proteins such as ATM, ATR, and CHK1/CHK2 are activated in response to DNA damage and initiate cell cycle arrest at key points (G1/S and G2/M transitions). This pause in cell division gives the cell time to repair the damage before continuing to replicate. If the damage is too severe, apoptosis may be triggered. Defects in these checkpoint proteins can result in the unregulated progression of damaged cells, leading to cancer.
14. Discuss the role of BRCA1 and BRCA2 in DNA repair and cancer prevention.
Answer: BRCA1 and BRCA2 are critical tumor suppressor genes involved in homologous recombination (HR), a DNA repair pathway that fixes double-strand breaks. These genes help ensure that DNA is repaired accurately, using the sister chromatid as a template. Mutations in BRCA1 or BRCA2 impair this repair mechanism, leading to an accumulation of DNA damage and genomic instability. This significantly increases the risk of cancers such as breast, ovarian, and prostate cancer. Individuals with BRCA1 or BRCA2 mutations are more likely to develop these cancers due to impaired DNA repair.
15. What is the relationship between DNA repair and the accumulation of mutations in cancer cells?
Answer: The inability of cells to properly repair DNA damage results in the accumulation of mutations, which can lead to cancer. When DNA repair mechanisms are compromised or overwhelmed, errors in DNA replication and damage accumulation occur. These mutations can affect tumor suppressor genes, oncogenes, and genes that regulate the cell cycle. As these mutations accumulate, the affected cells gain a survival advantage, leading to uncontrolled proliferation and cancer development.
16. How does telomere shortening contribute to DNA damage and cancer risk?
Answer: Telomeres are repetitive DNA sequences at the ends of chromosomes that protect the genetic material from degradation and fusion with other chromosomes. As cells divide, telomeres shorten, and this eventually leads to cellular senescence or apoptosis. In some cancer cells, telomerase is reactivated, which maintains telomere length and enables unlimited cell division. However, when telomeres shorten too much, chromosomal instability can occur, leading to DNA damage. Such instability increases the risk of mutations and cancer development.
17. Explain the role of DNA repair in preventing mutagenic effects caused by chemotherapy and radiation therapy.
Answer: Chemotherapy and radiation therapy are designed to induce DNA damage in cancer cells, leading to cell death. However, normal healthy cells can also be affected by these treatments. DNA repair mechanisms play a crucial role in repairing the damage caused by these therapies in healthy cells. For example, cells may use double-strand break repair mechanisms like homologous recombination or non-homologous end joining to fix radiation-induced damage. In some cases, cancer cells may develop resistance to treatment by enhancing their DNA repair capacity, making them harder to treat.
18. How does chromosomal instability contribute to the progression of cancer?
Answer: Chromosomal instability refers to the frequent changes in the structure and number of chromosomes within a cell. This instability is often caused by defective DNA repair mechanisms, such as impaired homologous recombination or faulty checkpoints. As a result, cancer cells acquire mutations that drive tumorigenesis. Chromosomal instability can lead to aneuploidy (abnormal chromosome numbers), which can promote the activation of oncogenes or inactivate tumor suppressor genes, contributing to uncontrolled cell growth and cancer progression.
19. What is the role of autophagy in DNA repair and cancer prevention?
Answer: Autophagy is a cellular process in which damaged or unnecessary cellular components are degraded and recycled. It also plays a protective role in DNA repair by removing damaged proteins and organelles, which can contribute to DNA damage. By maintaining cellular homeostasis and preventing the accumulation of toxic substances, autophagy helps preserve genomic integrity. Defects in autophagy can impair DNA repair, leading to genomic instability and increased cancer risk.
20. How can targeted therapies that enhance DNA repair mechanisms be used in cancer treatment?
Answer: Targeted therapies that enhance DNA repair mechanisms can be used to treat cancers with defective repair pathways. For instance, patients with BRCA1 or BRCA2 mutations may benefit from drugs like PARP inhibitors, which inhibit an alternative repair pathway called base excision repair. By inhibiting PARP, cancer cells with defective HR repair mechanisms become unable to repair DNA damage, leading to cell death. Such therapies exploit the concept of “synthetic lethality” and are an emerging approach in precision cancer treatment.
