DNA Repair Mechanisms and Mutation Effects

Comprehensive vocabulary flashcards reviewing DNA repair mechanisms, enzymatic pathways, genetic diseases, and mutation classifications from OPTO 5344.

Proofreading by DNA Polymerase

The primary cellular mechanism used during DNA replication to prevent errors, utilizing $3'$ to $5'$ exonuclease activity to detect and remove mismatched bases.

Superoxide Dismutase (SOD)

An enzyme that eliminates reactive oxygen species (ROS) to prevent oxidative DNA damage such as thymidine glycol or 8-oxo-dG formation.

Thymidine Glycol

A specific DNA lesion caused by oxidative stress that blocks DNA replication.

8-oxo-dG (8-Oxoguanine)

An oxidized form of guanine induced by reactive oxygen species that mispairs with adenine, resulting in $G\text{--}C$ to $T\text{--}A$ transversion mutations.

Cyclobutane Pyrimidine Dimer (CPD)

A bulky DNA lesion formed between adjacent pyrimidines due to UV radiation exposure that distorts the double helix structure.

CPD Photolyase

An enzyme utilizing visible light ($350\text{--}450 formulation nm$) to directly reverse UV-induced photodimers; absent in placental mammals.

Homology Dependent Repair

A repair strategy that uses the complementary undamaged strand as a template to remove and replace damaged DNA bases.

Non-bulky DNA Changes

Minor DNA alterations, such as depurination or deamination, that do not distort the overall double helix structure and are repaired by Base Excision Repair.

AP Site (Apurinic/Apyrimidinic Site)

A location in a DNA strand lacking a purine or pyrimidine base while keeping the sugar-phosphate backbone intact.

DNA Glycosylase

An enzyme in Base Excision Repair that cleaves the base-sugar bond to remove an altered base, leaving an apurinic site.

AP Endonuclease

An enzyme that cleaves the phosphodiester backbone at an AP site during Base Excision Repair.

dRpase (Deoxyribose Phosphodiesterase)

A prokaryotic enzyme in Base Excision Repair that cleaves phosphodiester bonds to excise adjacent backbone segments following an AP endonuclease cut.

DNA Polymerase $\beta$ (Pol B)

A eukaryotic DNA polymerase that synthesizes replacement DNA during Base Excision Repair, displacing the original strand.

Flap Endonuclease

A eukaryotic enzyme that clips off displaced single-stranded DNA flaps created during long-patch Base Excision Repair.

Base Excision Repair (BER)

A pathway that removes single damaged bases causing non-bulky changes using DNA glycosylases, AP endonuclease, DNA polymerase, and ligase.

Nucleotide Excision Repair (NER)

A repair mechanism that excises oligonucleotide segments containing bulky, helix-distorting DNA damage such as UV photodimers.

Global Genomic Repair (GGR)

An NER sub-pathway initiated by XPC and XPE that scans and repairs transcriptionally silent regions of the genome.

XPC and XPE

Xeroderma pigmentosum proteins responsible for recognizing damaged bases in non-transcribed genomic regions during Global Genomic Repair.

Transcription-Coupled NER (TC-NER)

A rapid NER pathway triggered when RNA polymerase encounters and stalls at a bulky DNA lesion during transcription.

CSA and CSB

Cockayne Syndrome proteins A and B that recognize stalled RNA polymerase complexes during Transcription-Coupled NER and recruit TFIIH.

TFIIH

A multiprotein transcription factor complex containing XPB and XPD helicases, recruited during NER to unwind DNA surrounding a lesion.

XPB and XPD

Xeroderma pigmentosum subunit helicases contained within TFIIH that unwind the DNA double helix around a damaged site during NER.

RPA (Replication Protein A)

A protein that binds to and stabilizes single-stranded DNA segments generated during Nucleotide Excision Repair.

PCNA (Proliferating Cell Nuclear Antigen)

A sliding clamp protein that recruits DNA polymerases $\delta$ and $\epsilon$ to synthesize repair patches in NER and Mismatch Repair.

Xeroderma Pigmentosum (XP)

A genetic disease caused by mutations in NER genes (e.g., XPB, XPD), producing severe UV sensitivity, elevated skin cancer rates, and ocular damage.

Mismatch Repair (MMR)

A post-replication process that corrects mispaired bases and small insertion/deletion loops escaped by DNA polymerase proofreading.

MutS

A bacterial protein (and eukaryotic homologue component) that detects base-pair mismatches and binds near the replication fork.

MutH

A prokaryotic MMR endonuclease that identifies methylated parent DNA strands and nicks the newly synthesized unmethylated daughter strand.

MutL

A matching protein in prokaryotic MMR that complexes with MutS to correctly position MutH at the mismatch site.

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

An inherited cancer predisposition syndrome caused by mutations in human genes homologous to prokaryotic MMR components MutS and MutL.

SOS System

An error-prone bacterial repair process of last resort that enables replication machinery to bypass lesions at stalled replication forks.

Cockayne Syndrome

A disorder caused by mutations in CSA or CSB genes leading to stalled RNA polymerase, apoptosis, short stature, premature aging, and retinal atrophy.

Trans-lesion Synthesis (TLS)

An error-prone bypass mechanism using specialized polymerases to replicate across unrepaired DNA lesions without correcting the original damage.

Bypass Polymerase

A low-fidelity DNA polymerase lacking $3'$ to $5'$ exonuclease proofreading (e.g., Pol V in prokaryotes) recruited by PCNA or $\beta$-clamp to bypass lesions.

Non-Homologous End Joining (NHEJ)

An error-prone double-strand break repair pathway that directly ligates broken DNA ends without requiring a homologous template sequence.

Ku70/80 Heterodimer

A protein dimer that binds broken double-stranded DNA ends during NHEJ, stabilizing them and recruiting downstream repair complex components.

Artemis

A nuclease recruited during Non-Homologous End Joining to trim damaged or mismatched DNA ends before ligation.

XRCC4

An X-ray repair protein that complexly interacts with DNA Ligase IV to rejoin DNA strands during Non-Homologous End Joining.

DNA Ligase IV

An enzyme specialized in sealing double-stranded breaks during Non-Homologous End Joining.

INDEL Mutation

An insertion or deletion mutation that routinely results from end processing in error-prone Non-Homologous End Joining.

Homologous Recombination (HR)

An accurate double-strand break repair pathway that utilizes an intact sister chromatid or homologous chromosome as a template.

D-loop (Displacement Loop)

A branched DNA structure created during homologous recombination when an invading single-stranded $3'$ tail displaces one strand of a homologous duplex.

Double-Strand Break Repair (DSBR)

A homologous recombination pathway featuring double D-loop capture and Holliday junctions that can yield crossover or non-crossover products.

Synthesis-Dependent Strand Annealing (SDSA)

A homologous recombination pathway where invading strands are displaced by helicase prior to ligation, exclusively forming non-crossover products.

Holliday Junction (HJ)

A four-way branched DNA structure formed during homologous recombination that must be enzymatically resolved.

Cytogenetic Location

The standard chromosomal address of a gene (e.g., Chr1p31.3) denoting chromosome number, arm, and specific band pattern.

P-arm

The short arm of a chromosome, designated by the letter p.

Q-arm

The long arm of a chromosome, designated by the letter q.

Centromere

The primary constricted region of a chromosome that separates the short (p) arm from the long (q) arm.

RPE65 Gene

A gene located at cytogenetic band Chr1p31.3 whose variants are assessed in genetic testing for retinal diseases.

c.1304A>G Mutation

Nomenclature indicating a single-base substitution of adenine (A) with guanine (G) at cDNA nucleotide position 1304.

p.Y435C Mutation

Protein nomenclature indicating that tyrosine (Y) is replaced by cysteine (C) at amino acid position 435.

Pathological Variant

A genetic sequence alteration confirmed or predicted to cause disease or impair normal protein function.

Variant of Unknown Significance (VUS)

A sequence change whose potential clinical impact on protein function or disease risk cannot be determined from available data.

Open Reading Frame (ORF)

A continuous sequence of codons starting with an initiation codon and ending at a stop codon, capable of translating into a polypeptide.

Conservative Amino Acid Substitution

A mutation replacing an amino acid with one of similar chemical properties, typically causing minimal alterations to protein structure or function.

Non-Conservative Amino Acid Substitution

A mutation replacing an amino acid with one of contrasting chemical properties, often resulting in significant functional or structural impairment.

Null Mutation

A mutation causing total loss of gene function or completely preventing the production of a protein product.

Leaky Mutation

A mutation causing partial loss of gene function, allowing the affected protein to retain reduced level of activity.

Synonymous (Silent) Mutation

A base pair alteration in a coding sequence that does not alter the encoded amino acid and leaves protein function unchanged.

Active Site Mutation

A mutation located within the catalytic or substrate-binding region of a protein, typically leading to a complete loss of function (null phenotype).

Promoter Mutation

A mutation in a non-coding regulatory sequence that alters transcription factor binding, leading to reduced, absent, or aberrantly timed gene expression.

Regulatory Gene Mutation

A mutation in a gene encoding a transcription factor or regulatory protein that alters the expression of multiple downstream target genes.

Splice Site Mutation

A mutation at an exon-intron boundary that alters pre-mRNA processing, frequently causing frameshifts, truncated proteins, or RNA degradation.

Direct Reversal Repair

A DNA repair class that directly restores damaged bases to their normal structures without excising nucleotides or breaking the phosphodiester backbone.

Reactive Oxygen Species (ROS)

Chemically reactive molecules (e.g., superoxide) capable of causing oxidative modifications to DNA bases such as guanine and thymine.

C to T Transition

The most frequent permanent nucleotide substitution resulting from unrepaired UV-induced photodimers.

Chromosome Ideogram

A visual diagram showing a chromosome's relative size, centromere location, p/q arms, and characteristic banding pattern.

End Resection

The enzymatic cleavage of $5'$ ends at double-strand breaks during homologous recombination to expose single-stranded $3'$ DNA tails.

Translocation

A structural chromosome mutation resulting from faulty double-strand break repair in which a DNA segment is relocated to a non-homologous chromosome.