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lecture recording on 26 February 2025 at 12.43.02 PM

Tumor Suppressor Genes and Mutations

  • Overview of BRCA1

  • Tumor suppressor gene that is frequently mutated in breast cancer patients.

  • Mutation Effects

  • A mutation in BRCA1 does not lead to more BRCA1 being produced (Option A); instead, it causes less BRCA1 to be made (Option B).

  • Consequence:

    • Reduced activity of BRCA1 leads to less suppression of tumors, thereby allowing increased tumor growth.

  • Proto-oncogenes

  • In contrast to tumor suppressors, mutations in proto-oncogenes can promote cell growth and cancer if activity is increased.

Loss of Function vs. Gain of Function Mutations

  • Types of Mutations

  • Loss of Function Mutation:

    • The protein does not perform its intended function.

    • Example: BRCA1 mutation where an early stop codon leads to a truncated protein.

  • Gain of Function Mutation:

    • A mutation that results in a protein acquiring new, often unintended functions, potentially promoting cancer.

Early Stop Codon Consequences

  • Impact on Gene and Protein

  • An early stop codon leads to truncated proteins, indicating a loss of function by producing proteins that cannot carry out their roles effectively.

  • This translates into enhanced cancer promotion due to compromised tumor suppression.

Understanding Stop Codons

  • Functions of Stop Codons:

  • Stop Translation:

    • Stop codons signal the ribosome to terminate protein synthesis (translation).

  • No Effect on Transcription:

    • Transcription is not halted by stop codons since RNA polymerase continues its function unaffected.

  • Replication Not Influenced:

    • DNA replication may proceed through mutated sites without issues in most cases.

Mutagens and Cancer Mutations

  • General Mechanism of Mutagens:

  • Mutagens can directly damage DNA, causing heritable mutations that contribute to cancer.

  • Examples of Common Mutagens:

    • Radiation: X-rays and UV light can induce DNA damage.

    • Chemicals: Cigarette smoke, preservatives, and acrylamide can alter DNA structure.

    • Infectious Agents: Such as HPV (head and neck cancers) and Helicobacter pylori (stomach cancer).

Specific Example: Acrylamide and Glycidomide

  • Risk of Glycidomide Mutation:

  • Glycidomide, derived from acrylamide, binds to DNA and causes mutations through added bulky structures disrupting normal base pairing.

  • Effect on Tumor Suppressor Gene P53:

    • Glycidomide can lead to a loss of function mutation in P53, which is a critical tumor suppressor gene.

    • This loss allows unchecked cell growth and cancer development.

Mechanisms of DNA Damage from Radiation

  • X-Rays:

  • Can break DNA's backbone, causing lethal and mutagenic effects if not repaired properly.

  • UV Radiation:

  • Can cause thymine dimers, leading to interruptions in DNA replication and subsequent mutations if not corrected.

DNA Replication Process

  • Enzymatic Actions in Replication:

  • DNA Polymerase: Separates DNA strands and synthesizes new complementary strands.

  • Effective replication requires coordination between leading and lagging strands, forming Okazaki fragments.

Distinction Between DNA Replication and Transcription

  • Purposes of Processes:

  • DNA Replication: Replicates DNA to ensure each daughter cell has the complete genome during cell division.

  • Transcription: Produces mRNA from DNA to create proteins.

Cellular Context for DNA Replication

  • DNA Replication Context:

  • Generally occurs in dividing cells, including stem cells and cancerous cells.

  • Most normal, non-dividing cells won’t actively replicate DNA to avoid mutational risks.

  • Chemotherapy: Targets rapidly dividing cells which often include some normal cells (side effects) alongside cancerous cells due to their high replication rates.