DNA Damage and Mutation

Comprehensive flashcards covering DNA damage, mutagens, repair mechanisms, and associated genetic diseases based on the Medical Genetics Lecture 5.

Mutation

Any heritable changes in the nucleotide sequence of DNA, which may occur in somatic cells or gametes.

Mutagens

Any agents which cause DNA damage, classified into biological, chemical, and physical categories.

Biological Mutagens

Agents including viruses and aflatoxin B1 (produced by certain fungi species) that can cause damage or lead to hepatocellular carcinoma.

Chemical Mutagens

Substances such as polycyclic aromatic hydrocarbons (found in tobacco smoke or burnt food), nitrous acid, and acridine dyes.

Physical Mutagens

Agents including X-rays, UV rays, and gamma rays that cause damage to DNA structure.

Somatic Mutations

Mutations occurring in non-reproductive cells that are not passed to offspring, such as those leading to melanoma or leukemia.

Germline Mutations

Mutations occurring in gametes (sperm or egg cells) that are passed on to offspring.

Depurination

A spontaneous process occurring at a rate of $10,000$ per cell per day where the base pops off the nucleotide, leaving a missing base in the DNA backbone.

Deamination

A spontaneous process involving the removal of an amino ($NH_2$) group; for example, converting cytosine to uracil ($C \to U$).

Thymine Dimers

Two adjacent thymines bonded together by exposure to UV light, which interferes with DNA replication and gene expression.

The 4 R’s of DNA Repair

The four basic steps in the repair process: (1) Recognize, (2) Remove, (3) Re-synthesize, and (4) Re-ligate.

Nucleotide Excision Repair (NER)

A mechanism used to fix thymine dimers involving excinuclease, DNA polymerase, and DNA ligase; deficiency causes Xeroderma pigmentosum.

Xeroderma Pigmentosum (XP)

A hereditary disorder caused by a deficit in proteins involved in Nucleotide Excision Repair (NER), leading to extreme UV sensitivity, freckling, and high skin cancer incidence.

Base Excision Repair (BER)

A repair system for single base alterations like cytosine deamination, utilizing DNA glycosylase and AP endonuclease.

DNA Glycosylase

An enzyme in Base Excision Repair that recognizes specific damaged bases (like uracil) and cuts them out, leaving the unpaired healthy base.

Mismatch Repair (MMR)

A system that identifies and fixes rare replication errors that escape proofreading using Mut proteins; deficiency leads to Lynch syndrome.

Homologous Recombination (HR)

A conservative double-strand break repair mechanism that uses the intact homologous chromosome as a template for accurate alignment.

Non-homologous End Joining (NHEJ)

A non-conservative double-strand break repair mechanism that uses a "best guess" approach to ligate strands back together, making it highly error-prone.

Nonionizing Radiation

Radiation like UVA/UVB that excites electrons but does not break covalent bonds, causing pyrimidine (thymine) dimers.

Ionizing Radiation

Radiation like UVC and X-rays that ejects electrons to form free radicals, causing single-strand breaks (SSBs) and double-strand breaks (DSBs).

Hereditary Polyposis Colon Cancer (Lynch syndrome)

A disorder caused by defective mismatch repair (hMSH1 and hMSH2 genes), increasing risk for colon, endometrial, and pancreatic cancers.

Transitions

A point mutation that replaces one purine for another purine (e.g., $A \to G$) or one pyrimidine for another pyrimidine (e.g., $C \to T$).

Transversions

A point mutation that replaces a purine for a pyrimidine or vice-versa.

Silent Mutation

A base-pair substitution where the new codon specifies the same amino acid, resulting in no change to the protein.

Missense Mutation

A mutation where a new codon specifies a different amino acid, which can significantly affect protein structure and function.

Nonsense Mutation

A mutation that converts an amino acid codon into a stop codon, resulting in a shortened (truncated) and usually nonfunctional protein.

Sense Mutation

A rare mutation where a stop codon is converted into an amino acid codon, resulting in a slightly longer protein.

Sickle Cell Disease

A condition caused by a single nucleotide substitution ($GAG \to GUG$) changing glutamic acid to valine in the beta-globin gene.

Frameshift Mutation

The insertion or deletion of one or more nucleotides (not in multiples of three) that alters the reading frame of translation.

Splicing Mutations

Mutations that alter the GT start or AG end of introns, preventing correct intron removal and resulting in different polypeptides.

Ataxia Telangiectasia (AT)

A disorder caused by a defective ATM gene, leading to sensitivity to ionizing radiation and lymphoreticular neoplasms.

Fanconi's Anemia

A condition involving a defect in DNA cross-link repair, associated with chromosomes 20q and 9q and an increased occurrence of cancer.

Bloom's Syndrome

A syndrome caused by defects in DNA ligase or Helicase (gene on 15q), resulting in lymphoreticular malignancies.

Cockayne Syndrome

A condition involving defective transcription factor II H in the NER mechanism, characterized by stunted growth and intellectual disability.

Aneuploidy

Numerical chromosomal abnormalities including Monosomy, Trisomy, and Tetrasomy.