DNA Repair and Associated Diseases

DNA Repair

• Double-strand DNA breaks can be repaired by homologous recombination or non-homologous end joining.
• Mutations result from spontaneous replication errors, chemical agents, and physical agents.
• Beneficial mutations can provide genetic variability and contribute to the antibody repertoire.
• Pathological mutations can lead to diseases and cancer.
• DNA repair mechanisms include excision repair (BER and NER), mismatch repair, and repair of single- or double-strand DNA breaks.

DNA Repair Diseases

• Ataxia telangiectasia is caused by a loss-of-function mutation in the ATM gene, encoding a protein that activates DNA repair.
• Werner syndrome (progeria) is caused by a mutation in a helicase/exonuclease required for telomere maintenance.
• Xeroderma pigmentosum is caused by a dysfunctional DNA repair system, leading to sensitivity to UV light.

DNA Replication

• The abasic sugar-phosphate unit is unstable and degrades, resulting in a single nucleotide gap in the DNA strand.
• Cells can repair this type of damage quickly and precisely, making it rarely mutagenic.

Genotoxic Environmental Agents

• Carcinogens cause tumorigenic transformation and the initiation of tumors.
• Oncogenes support the proliferation, survival, and evolution of tumor cells.
• Mutagens cause mutations, but not necessarily carcinogenic or oncogenic.
• Teratogens cause developmental abnormalities in embryos and fetuses.
• Clastogens cause chromosomal breaks.

Point Mutations in the Coding DNA Region

• Synonomous mutations result in different codons but encode the same amino acid.
• Non-synonymous mutations result in different codons that encode different amino acids, potentially affecting protein function.
• Nonsense mutations create a stop codon, resulting in a shorter, truncated protein.
• Readthrough mutations eliminate a stop codon, potentially extending the protein.

Indel Mutations in the Coding Region

• 1-2 basepair deletions or insertions (or multiples) cause a translation frameshift, leading to a garbled amino acid sequence and premature stop codon.
• 3 bp deletions or insertions (or multiples) remove or insert entire codons, potentially affecting amino acid sequence and protein function.

Mutations

• Mutations are small alterations in the DNA sequence affecting a few nucleotides.
• They occur randomly due to environmental agents or replication errors.
• Mutations are sometimes necessary and natural in the body, such as in antibody-coding genes.
• Mutations contribute to the variability of amino acid sequences in antibodies.

Chromosomal Alterations

• Recombination, including the exchange of DNA regions with homologous sequences, can occur during meiosis and DNA repair.
• Chromosomal aberrations, such as deletions, inversions, translocations, and amplifications, can affect large regions of DNA.
• Chromosome copy number changes are discussed in detail in Genetics.
• Chromosomal translocations can lead to oncogenes and diseases such as leukemia (e.g., Philadelphia chromosome).

Types of Mutations

• Point mutations involve the alteration of a single nucleotide.
• Transitions involve purine-purine or pyrimidine-pyrimidine changes (e.g., adenine to guanine, cytosine to thymine).
• Transversions involve purine-pyrimidine or pyrimidine-purine changes (e.g., adenine to cytosine, thymine to guanine).
• Insertions or deletions (indels) involve the insertion or deletion of one or a few nucleotides.

Explore the fascinating mechanisms of DNA repair, including homologous recombination and non-homologous end joining. This quiz covers various mutations, their impact on genetic variability and diseases like Ataxia telangiectasia and Xeroderma pigmentosum. Test your understanding of DNA replication and the significance of repair mechanisms.