DNA Mutation and DNA Repair

Comprehensive vocabulary flashcards covering point mutations, non-coding mutations, chromosomal aberrations, spontaneous and induced DNA damage, mutagens, the Ames test, and excision, double-strand break, and homologous recombination repair pathways.

Mutation

A heritable change in the DNA sequence that serves as the ultimate source of all allelic variation.

Point Mutation

A mutation that involves a change in a single base pair within the DNA sequence.

Tautomeric Shift

A rare, temporary spontaneous change in base chemical structure where hydrogen bonds change positions, allowing abnormal base pairing (such as cytosine pairing with adenine or guanine pairing with thymine) if present during DNA replication.

Silent Mutation

A base substitution within a coding sequence that does not alter the amino acid sequence because the genetic code is redundant.

Missense Mutation

A base substitution within a coding sequence that alters a single codon to encode a different amino acid, having a neutral or inhibitory effect on protein function.

Nonsense Mutation

A base substitution within a coding sequence that changes a normal codon into a premature stop codon, terminating translation early and generally inhibiting protein function.

Frameshift Mutation

The insertion or deletion of a number of nucleotides that is not divisible by 3 in a coding sequence, altering the reading frame distal to the mutation and almost always resulting in a nonfunctional protein.

Promoter Mutation

A mutation occurring in a gene's promoter region that may increase or decrease the rate of transcription.

Regulatory Element/Operator Site Mutation

A mutation outside a coding region that disrupts the proper regulation of gene expression.

$5'\text{-UTR} / 3'\text{-UTR}$ Mutation

A mutation in the untranslated regions of an mRNA that may alter its translation efficiency or stability.

Splice Recognition Sequence Mutation

A mutation at a splice site that may alter the proper splicing of pre-mRNA.

Wild Type

The most prevalent genotype or phenotype observed within a natural population.

Mutant Allele

A rare allele in which the nucleotide sequence of the wild-type allele has been altered.

Reverse Mutation

A mutation that changes a mutant allele back into the wild-type allele.

Deleterious Mutation

A mutation that decreases the chance of survival of an organism.

Lethal Mutation

A mutation that results in the death of a cell or an entire organism.

Beneficial Mutation

A mutation that enhances the survival or reproductive success of an organism.

Conditional Mutation

A mutation in which the mutant phenotype is expressed only under certain environmental conditions.

Germ-Line Mutation

A mutation that occurs directly in a sperm, egg, or gamete precursor cell, passing into all cells of the offspring and to future generations.

Somatic Mutation

A mutation that occurs in a non-germline body cell, affecting only a patch of tissue in the individual and not transmitted to future generations.

Pericentric Inversion

A chromosomal inversion resulting from a double-strand break in which the inverted segment includes the centromere.

Paracentric Inversion

A chromosomal inversion resulting from a double-strand break in which the inverted segment excludes the centromere.

Reciprocal Translocation

A structural chromosomal change where two nonhomologous chromosomes exchange segments following double-strand breaks without any loss of genetic material.

Robertsonian Translocation

A translocation occurring from double-strand breaks near the centromeres of two acrocentric chromosomes, fusing the long arms into a single metacentric chromosome with the loss of the short arms.

Depurination

A spontaneous reaction with water that breaks the covalent linkage between a purine base (adenine or guanine) and deoxyribose, releasing ~$10{,}000$ purines per cell every 24 hours and creating an apurinic site.

Deamination

The spontaneous or chemical removal of an amino group from a base; cytosine deamination yields uracil (which pairs with adenine), whereas 5-methylcytosine deamination yields thymine.

Reactive Oxygen Species (ROS)

Chemically reactive molecules containing oxygen and often an unpaired electron (such as hydrogen peroxide, superoxide, and hydroxyl radicals) produced by cellular respiration that cause oxidative damage to DNA, proteins, and lipids.

Nitrous Acid

A chemical mutagen that deaminates bases by replacing amino groups with keto groups, converting cytosine to uracil, adenine to hypoxanthine, and guanine to xanthine.

Alkylating Agents

Chemical mutagens (e.g., mustard gas, ethyl methanesulfonate [EMS], and ethyl ethane sulfonate [EES]) that covalently add alkyl groups to bases, altering base pairing (e.g., 7-ethylguanine pairing with thymine) or inducing crosslinks and chromosome breaks.

Ionizing Radiation

High-energy, short-wavelength radiation (such as X-rays and gamma rays) that penetrates deep into tissues, generates free radicals, and causes base deletions, single-strand breaks, double-strand breaks, and crosslinks.

Non-Ionizing Radiation

Lower-energy radiation (such as UV light) that penetrates surfaces and induces covalent linkage between adjacent pyrimidines, creating thymine dimers.

Thymine Dimer

A covalent linkage formed between adjacent thymine bases on a DNA strand due to UV radiation that distorts the double helix and prevents proper base-pairing during replication.

Ames Test

A biological assay using histidine-auxotrophic Salmonella typhimurium carrying a frameshift mutation to assess the mutagenic capability of a compound by measuring its reversion rate to histidine independence ($his^+$).

Direct Repair

A repair pathway where an enzyme directly reverses an incorrect structural alteration in a base back to its native form without excising DNA.

Base Excision Repair (BER)

A multistep repair pathway for non-helix-distorting base damage where a DNA N-glycosylase removes the damaged base, AP endonuclease nicks the backbone, DNA polymerase replaces the nucleotide, and DNA ligase seals the nick.

DNA N-glycosylase

An enzyme in base excision repair that recognizes an abnormal base and cleaves the glycosidic bond connecting it to deoxyribose, generating an apurinic or apyrimidinic (AP) site.

AP Endonuclease

An enzyme in base excision repair that initiates the removal of the sugar-phosphate backbone by making a single-strand nick $5'$ to an apurinic or apyrimidinic site.

Nucleotide Excision Repair (NER)

A repair pathway that removes bulky, helix-distorting DNA lesions (such as thymine dimers) by excising a short oligonucleotide segment flanking the distortion and resynthesizing it using the complementary strand.

Mismatch Repair (MMR)

A repair system that recognizes incorrectly incorporated base pairs missed by proofreading exonuclease, targeting the newly synthesized daughter strand prior to full methylation when it is still hemimethylated.

Nonhomologous End Joining (NHEJ)

An error-prone repair mechanism available at all stages of the cell cycle that glues double-strand break ends back together without using a homologous template, frequently causing nucleotide deletions or insertions.

Ku70/80 Heterodimer

A ring-shaped protein complex that binds directly to DNA ends at a double-strand break, stabilized by PAXX, to recruit repair factors including DNA-PKcs and Artemis.

DNA-PKcs

A serine/threonine protein kinase catalytic subunit that binds the Ku70/80 heterodimer to bridge broken ends and phosphorylates Artemis to activate its nuclease activity.

Artemis

A DNA processing nuclease recruited by Ku70/80 and activated via phosphorylation by DNA-PKcs; exhibits $5'$ endonuclease activity to blunt ends and $3'$ endonuclease activity to leave a $4\,\text{nt}$ $3'$ overhang.

Homology Directed Repair (HDR)

An error-free double-strand break repair pathway occurring in the S and G2 phases of the cell cycle that uses an undamaged homologous sister chromatid as a repair template.

MRN Complex

A protein complex consisting of Mre11 (nuclease activity), Rad50 (ATPase activity), and Nbs1 (protein-protein interactions) that detects double-strand breaks, initiates end resection, and recruits ATM.

Microhomology-Mediated End Joining (MMEJ)

An error-prone double-strand break repair pathway operating during S/G2 phase that requires short-range resection (~$20\,\text{nt}$) and aligns 5 to 25 bp microhomologous sequences, followed by flap removal and ligation.

Ataxia Telangiectasia Mutated (ATM)

A protein kinase recruited by the MRN complex to double-strand breaks that phosphorylates the histone variant H2A.X and MDC1 to coordinate downstream damage signaling.

Histone Variant H2A.X

A core histone variant encoded by 1 gene in humans that plays a critical role in DNA repair by being phosphorylated by ATM at sites of double-strand breaks.

BRCA1

A tumor suppressor protein recruited to double-strand breaks by the MRN complex that promotes homology directed repair (by recruiting BRCA2 via PALB2) and inhibits NHEJ.

53BP1

A p53 binding protein recruited to double-strand breaks that delays the cell cycle, promotes nonhomologous end joining, and inhibits homology directed repair when bound.

Rad51

A recombinase that forms long helical filaments on single-stranded DNA to mediate homology searching and strand invasion into the undamaged sister chromatid during HDR.

Replication Protein A (RPA)

A single-stranded DNA-binding protein that binds and protects single-stranded DNA overhangs generated during end resection from premature degradation until displaced by Rad51.