Questions and Answers
What is the significance of repairing mutations before DNA replication, and what can happen if they are not repaired?
Repairing mutations before DNA replication prevents the locking in of errors, which can lead to lethal events or the propagation of faulty genetic information.
Why is uracil considered a poor alternative to thymine as the fourth base in DNA?
Uracil is less stable than thymine and can lead to mispairing and mutations due to its lower specificity in base pairing.
Describe the types of mutations that can occur and give an example of each type.
Types of mutations include silent mutations (no change in amino acid), nonsensical mutations (premature stop codon), missense mutations (different amino acid), and structural changes like deletions, insertions, inversions, or translocations.
How do mutations in repair pathway genes contribute to cancer progression?
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What role do cytochrome P450 enzymes play in the Ames test, and how can one interpret its results?
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What is the primary role of DNA glycosylases in the DNA repair process?
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Describe the impact of mismatch repair (MMR) on DNA replication fidelity.
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How does nucleotide excision repair (NER) address UV-induced damage in DNA?
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What is the consequence of ssDNA breaks if left unrepaired by PARP inhibitors in cancer cells?
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What are the roles of Ku proteins and DNA-dependent protein kinase in non-homologous end joining (NHEJ)?
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Study Notes
Mutations
- Cells experience billions of mutations per generation, mainly arising from DNA replication errors and exposure to mutagens.
- Mutations must be repaired before DNA replication to prevent permanent changes or lethal outcomes.
- Classes of mutagens include chemical agents, radiation, and biological factors.
- Uracil is not suitable as a base in DNA due to its potential for pairing errors, while 5’-methylcytosine is prone to mutation.
- Humans show considerable genetic variation, with cancerous cells exhibiting complex and numerous mutations.
- Types of mutations encompass silent, nonsense, missense, deletions, insertions, inversions, and translocations.
- Cancer progression often involves mutations in repair pathway genes, where loss of function contributes significantly, along with epigenetic silencing of repair genes.
- Familiarize with specific genes and their associated conditions, including mismatch repair genes, Xeroderma Pigmentosum (XP), BRCA1 & BRCA2, and others linked to cancer syndromes.
Repair of Mutations
- Understand major DNA repair pathways and their associated mutations, as well as diseases linked to their dysfunction.
- Direct repair does not involve base replacement; enzymes like photolyase and O6-methylguanosine transferase perform this function.
- Base Excision Repair (BER) addresses point mutations and base alterations, using DNA glycosylases to excise damaged bases, followed by endonuclease cleavage and repair synthesis.
- Mismatch Repair (MMR) fixes DNA polymerase misincorporations, enhancing replication fidelity by recognizing and correcting errors. Related to disorders like Lynch syndrome and Huntington’s disease.
- Nucleotide Excision Repair (NER) deals with bulky DNA damage, such as thymine dimers caused by UV light; associated conditions include Xeroderma Pigmentosum.
- Intra-strand crosslink repair (ICL) relies on the Fanconi complex, which assembles at stalled forks to facilitate repair through translesion DNA polymerases.
- Single-strand DNA break repair utilizes PARP enzymes to recognize damage and recruit repair machinery, with inhibitors showing promise in certain breast cancers.
- Double-strand DNA break repair is critical, with two main pathways:
- Non-Homologous End Joining (NHEJ) can be mutagenic due to possible chromosome translocations.
- Homologous recombination uses an undamaged chromosome as a template, involving proteins like Rad51 and BRCA1 & 2, which are critical in breast cancer repair.
- Translesion synthesis allows polymerases to bypass unrepaired damage, enabling replication to proceed with potentially mutagenic consequences.
- DNA Damage Response (DDR) is a complex network of proteins that detect DNA damage (e.g., ATM, ATR) and coordinate repair processes, block cell cycling, and transcription of repair genes.
- Chemotherapeutic strategies, such as PARP inhibitors, target specific repair pathways in cancer cells, causing accelerated damage while sparing healthy cells that possess multiple repair mechanisms.
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Description
Explore the fascinating world of mutations in cells, including their origins and types. This quiz covers the critical repair mechanisms necessary to prevent permanent changes caused by mutations and their implications in cancer. Test your knowledge of mutagens and genetic variations linked to significant health conditions.
