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.