TOPIC 5 BS1030: CONSEQUENCES OF MUTATIONS (LECTURE 2)

What is a mutation?

A permanent change in the DNA sequence.

What is mutagenesis?

The process by which mutations occur, naturally or due to mutagens.

What is the difference between germline and somatic mutations?

Germline: occurs in gametes, inherited by offspring, present in every cell. Somatic: occurs in body cells, not inherited, may affect only one cell or tissue.

What are point mutations?

Mutations affecting one or a few nucleotides in a gene.

What is a missense mutation?

Codon changes → codes for a different amino acid; effect is variable.

What is a nonsense mutation?

Codon becomes a premature stop codon → truncated protein; usually severe.

What is a silent mutation?

Codon changes but codes for the same amino acid → usually no effect.

What is a frameshift mutation?

Insertion or deletion of nucleotides not in multiples of three → shifts reading frame → often severe.

What are transitions and transversions?

Transition: purine ↔ purine (A↔G) or pyrimidine ↔ pyrimidine (C↔T). Transversion: purine ↔ pyrimidine (A/G ↔ C/T).

How does sickle-cell anaemia occur?

Single point transversion mutation (A→T) in β-globin gene → Glu → Val → HbS → sickle-shaped RBCs.

What are the clinical effects of sickle-cell anaemia?

Anaemia (RBC rupture), Pain (capillary blockage), Organ damage, Fatigue, dizziness, shortness of breath.

How is sickle-cell allele related to malaria?

Heterozygotes (sickle-cell trait) are resistant to malaria; natural selection maintains allele in certain populations.

What is a deletion mutation?

Loss of nucleotides → protein missing amino acids.

What are chromosomal mutations?

Large-scale changes in chromosome structure → can create fusion genes.

What causes DNA damage?

Spontaneous mutations, Exogenous factors (UV, ionising radiation), Endogenous factors (replication errors).

What is tautomerism?

Temporary shift in a base's hydrogen → mispairing during replication → point mutation.

What is depurination?

Loss of a purine base (A/G) → AP site → incorrect base insertion if unrepaired.

What is deamination?

Removal of amino group from a base.

How does UV radiation damage DNA?

Forms pyrimidine dimers (usually T-T) → blocks replication → mutations.

How does ionising radiation damage DNA?

Causes strand breaks (single & double) and ring opening → severe mutations.

How do intercalating agents affect DNA?

Insert between bases → polymerase slips → frameshift mutations.

How do anti-cancer drugs damage DNA?

Induce strand breaks, crosslinks, or inhibit replication → kills rapidly dividing cells.

What are replication errors?

Mismatches, insertions, or deletions during DNA replication.

Why are frameshift mutations so severe?

Shift the reading frame → all downstream codons altered → usually non-functional protein.

How do mutations contribute to cancer?

Mutations in tumour suppressor genes, DNA repair genes, and oncogenes can lead to cancer.

What is the multi-step model of carcinogenesis?

Cancer develops through the accumulation of multiple mutations over time.

What advantage does each mutation provide to a cell?

Each mutation gives the cell a small growth advantage.

List three capabilities that successive mutations allow a cancer cell to acquire.

1. Divide uncontrollably 2. Evade apoptosis 3. Invade surrounding tissues

What role does DNA polymerase play in DNA replication?

DNA polymerase has proofreading abilities, but errors can still occur.

What happens if replication errors occur in critical genes?

They can initiate cancer if they affect tumor suppressors, oncogenes, or DNA repair genes.

Name a tumor suppressor gene that can be affected by replication errors.

p53

Name an oncogene that can be affected by replication errors.

RAS

What is the function of base excision repair (BER)?

BER fixes single damaged bases in DNA.

What does nucleotide excision repair (NER) repair?

NER repairs bulky lesions, such as UV dimers.

What does mismatch repair (MMR) correct?

MMR corrects replication errors.

What is the consequence of defective DNA repair mechanisms?

Defective mechanisms lead to increased mutation rates and genomic instability.

What syndrome is associated with defective mismatch repair?

Lynch syndrome (HNPCC), which can lead to colon cancer.

What mutations are associated with breast and ovarian cancer?

BRCA1 and BRCA2 mutations, which affect homologous recombination.

How do mutations in DNA repair genes affect cancer development?

They increase mutation frequency across the genome and can accelerate cancer development.

What is a paradoxical effect of certain mutations in tumors?

They can make tumors more resistant to therapy or more sensitive to specific drugs, like PARP inhibitors.

Which cancer types are associated with mutations in the MLH1 and MSH2 genes?

Colon and endometrial cancers.

What is the role of double-strand break repair mechanisms?

They fix breaks in DNA strands through homologous recombination or non-homologous end joining (NHEJ).

What is the key point regarding effective DNA repair?

Effective DNA repair prevents mutations from becoming permanent, reducing cancer risk.

What is the relationship between genomic instability and cancer progression?

Increased genomic instability leads to more mutations in oncogenes and tumor suppressors, promoting cancer progression.

What is the significance of the TP53 gene in cancer?

Mutations in TP53 are associated with multiple cancers due to defective damage response.

Why does cancer incidence increase with age?

Cancer usually requires multiple mutations to accumulate over time in key genes, and older individuals have had more cell divisions, leading to more opportunities for mutations.

What happens to cancer incidence in the very elderly?

Cancer incidence declines in the very elderly due to fewer actively dividing cells, which reduces the chances for mutations to occur.

What are oncogenes?

Oncogenes are genes that, when mutated, can promote cancer growth.

What role do tumor suppressor genes play in cancer?

Tumor suppressor genes normally inhibit cell division; mutations can lead to uncontrolled cell growth.

What is the significance of DNA repair genes in cancer?

DNA repair genes help fix mutations; when they are mutated, it increases the risk of cancer.

What is the Warburg effect?

The Warburg effect refers to cancer cells using aerobic glycolysis for energy, supporting rapid growth.

What are the hallmarks of cancer?

Common features of cancer cells include sustained proliferation, evasion of apoptosis, altered metabolism, manipulation of the tissue microenvironment, and metastasis.

How do cancer cells sustain proliferation?

Cancer cells divide faster than normal and resist growth arrest, allowing them to continue proliferating.

What is meant by 'evading apoptosis' in cancer cells?

Cancer cells ignore signals that normally trigger cell death, allowing damaged cells to survive.

What is angiogenesis in the context of cancer?

Angiogenesis is the process by which cancer cells promote the growth of new blood vessels to supply nutrients and oxygen.

What does it mean for cancer cells to metastasize?

Metastasis is the process by which cancer cells leave their original tissue and spread to grow in foreign tissues.

How can scientists study the effects of specific mutations?

Scientists can engineer specific mutations into cloned genes to observe their effects on protein function and cancer-like behavior.

What is the relationship between cell division and cancer risk?

More cell divisions increase the likelihood of mutations accumulating, which raises cancer risk.

Why do older individuals have a higher risk of cancer?

Older individuals have had more time for mutations to accumulate due to more cell divisions over their lifetime.