Chapter 10: DNA Mutability and Repair
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Questions and Answers

Mutations at protein coding sequences or DNA regions that control mRNA expression can change the ______ of a cell.

phenotypes

Inaccuracy in DNA replication is one of the important sources of ______.

mutations

A critical function of DNA repair mechanisms is to prevent errors in DNA ______ or transcription.

replication

The simplest mutations include transitions, transversions, and ______ or deletions of a single nucleotide.

<p>insertions</p> Signup and view all the answers

Biodiversity depends on a balance between ______ and repair of DNA.

<p>mutation</p> Signup and view all the answers

Exonuclease VII or RecJ degrades DNA in a 5’ to 3’ direction when DNA is cleaved on the ______ side of the mismatch.

<p>5'</p> Signup and view all the answers

If the nick is on the 3’ side, ______ is the exonuclease that degrades DNA in a 3’ to 5’ direction.

<p>Exonuclease I</p> Signup and view all the answers

In eukaryotic cells, MSH protein is a homolog of ______.

<p>MutS</p> Signup and view all the answers

Mutations can occur from damage to DNA and errors in ______.

<p>replication</p> Signup and view all the answers

Environmental factors such as ______ can cause DNA damage.

<p>radiation</p> Signup and view all the answers

The most frequent and important kind of hydrolytic damage involves the deamination of the base ______.

<p>cytosine</p> Signup and view all the answers

Deamination of adenine produces ______, which can hydrogen bond to cytosine.

<p>hypoxanthine</p> Signup and view all the answers

DNA has thymine instead of ______ to help maintain its stability and integrity.

<p>uracil</p> Signup and view all the answers

Thymine dimers can block DNA replication and ______.

<p>transcription</p> Signup and view all the answers

Deamination of cytosine causes a C:G to ______ transition mutation.

<p>T:A</p> Signup and view all the answers

Excision repair removes the damaged ______ from the DNA.

<p>nucleotide</p> Signup and view all the answers

Translesion Polymerase synthesizes DNA across the site of the ______.

<p>damage</p> Signup and view all the answers

Photolyase captures energy from ______ to break covalent bonds linking pyrimidines.

<p>light</p> Signup and view all the answers

A methyltransferase removes the methyl group from ______.

<p>methylguanine</p> Signup and view all the answers

Base excision repair involves glycosylase hydrolyzing the ______ bond.

<p>glycosidic</p> Signup and view all the answers

Nucleotide excision repair recognizes distortions to the shape of the double ______.

<p>helix</p> Signup and view all the answers

Extensive insertions or deletions and gross rearrangements of chromosome ______ cause more drastic changes in DNA.

<p>structure</p> Signup and view all the answers

The spontaneous mutation rate ranges from 10-6 to 10-______ per round of DNA replication.

<p>11</p> Signup and view all the answers

DNA microsatellites are examples of ______ that have repeats of di-, tri-, or tetranucleotide sequences.

<p>mutations</p> Signup and view all the answers

Some replication errors escape ______ due to the limitations of the proofreading function.

<p>proofreading</p> Signup and view all the answers

Mismatch repair increases the accuracy of DNA synthesis by correcting ______ that escape proofreading.

<p>mismatches</p> Signup and view all the answers

In E. coli, the MutS dimer detects mismatches and induces a conformational change in ______.

<p>MutS</p> Signup and view all the answers

Dam methylase adds a methyl group on ______ residues to help identify parental strands during repair.

<p>A</p> Signup and view all the answers

MutH binds at ______ sites to initiate the mismatch repair process.

<p>hemimethylated</p> Signup and view all the answers

UvrA and UvrB scan the ______

<p>DNA</p> Signup and view all the answers

UvrC creates two incisions, one located 4~5 nts ______ and the other 8 nts 5’ to the lesion.

<p>3’</p> Signup and view all the answers

UvrD is known as a DNA ______.

<p>helicase</p> Signup and view all the answers

RNA polymerase stalls when it detects ______ in the DNA.

<p>damage</p> Signup and view all the answers

TFIIH unwinds the DNA template and includes ______ and XPD for helicase activity.

<p>XPA</p> Signup and view all the answers

Non-homologous end joining (NHEJ) protects and processes the broken ______.

<p>ends</p> Signup and view all the answers

Excision repair uses undamaged DNA as a ______.

<p>template</p> Signup and view all the answers

DSBs are the most ______ of all DNA damage.

<p>cytotoxic</p> Signup and view all the answers

The proteins involved in Non-homologous end joining (NHEJ) include Ku70, Ku80, DNA-PKcs, and ______.

<p>Artemis</p> Signup and view all the answers

DNA-PKcs forms a complex with ______.

<p>Artemis</p> Signup and view all the answers

The ligation during NHEJ is performed by Ligase IV, XRCC4, and ______.

<p>XLF</p> Signup and view all the answers

Translesion synthesis is a highly ______ mechanism of DNA damage tolerance.

<p>error-prone</p> Signup and view all the answers

In E. coli, DNA pol IV is also known as ______.

<p>DinB</p> Signup and view all the answers

Translesion DNA polymerase must be tightly ______ due to its mutagenic nature.

<p>regulated</p> Signup and view all the answers

The SOS response in E. coli leads to the expression of translesion DNA polymerases after ______.

<p>DNA damage</p> Signup and view all the answers

Human DNA pol η inserts two ______ residues opposite a thymine dimer.

<p>A</p> Signup and view all the answers

Flashcards

DNA Replication Errors

Mistakes made during DNA replication that lead to permanent changes in the DNA sequence.

Mutations

Permanent changes in the DNA sequence.

Point Mutation

A type of mutation where a single nucleotide is inserted or deleted.

Transitions (Mutation)

Mutations where a pyrimidine replaces another pyrimidine or a purine replaces another purine.

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Transversions (Mutation)

Mutations where a pyrimidine replaces a purine or vice versa.

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Spontaneous mutation rate

The frequency of mutations occurring naturally during DNA replication, typically in the range of 10⁻⁶ to 10⁻¹¹ per round.

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Mutation hotspot

A region of DNA where mutations occur at a higher frequency than average.

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DNA microsatellites

Short, repeating sequences of DNA (e.g., di-, tri-, or tetranucleotide repeats), often prone to mutation.

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Mismatch repair system

A cellular process that corrects errors in DNA replication that evade proofreading.

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Proofreading function (3' to 5' exonuclease)

Part of DNA replication machinery that checks newly synthesized DNA for errors and removes incorrectly incorporated nucleotides.

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MutS

Part of the mismatch repair system; a protein that detects mismatched bases and initiates the repair process.

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Dam methylase

An enzyme that adds a methyl group to specific DNA sequences (GATC).

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Hemimethylated DNA

DNA where only one strand of a GATC sequence is methylated.

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Nucleotide excision repair

A DNA repair pathway that removes damaged or incorrect nucleotides from DNA.

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UvrA and UvrB

Proteins in E. coli that scan DNA for damage.

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UvrC

An enzyme in E. coli that cuts out damaged DNA.

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UvrD

A DNA helicase in E. coli that removes the damaged strand.

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XPC

A protein in eukaryotes that detects distortions in the DNA helix.

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ERCC1-XPF

An enzyme in eukaryotes that cuts 5' to the lesion in DNA.

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XPG

An enzyme in eukaryotes that cuts 3' to the lesion in DNA.

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Transcription-coupled repair

A specialized DNA repair pathway that repairs DNA damage that blocks RNA polymerase.

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Mismatch Repair (MMR)

A cellular process that corrects errors in DNA replication, primarily mismatched base pairs, that are missed by DNA polymerase. Involves recognizing and removing the incorrect base, followed by resynthesis of the correct sequence.

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DNA Damage Consequences

DNA damage can disrupt essential cellular processes, such as replication and transcription, or lead to mutations.

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Exonuclease VII or RecJ

Exonucleases that degrade DNA in a 5' to 3' direction, removing single-stranded DNA between a nick and a mismatch. They are used when the nick is on the 5' side of the mismatch.

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Thymine Dimers

Covalent bonds form between adjacent thymine bases, distorting the DNA structure and blocking replication and transcription.

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Deamination of Cytosine

Cytosine loses an amine group, converting it to uracil, which pairs with adenine instead of guanine, causing a C:G to T:A mutation.

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Exonuclease I

An exonuclease that degrades DNA in a 3' to 5' direction, removing single-stranded DNA between a nick and a mismatch. It is used when the nick is on the 3' side of the mismatch.

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MSH Protein

A protein involved in MMR in eukaryotes, homologous to the MutS protein in bacteria. It recognizes and binds to mismatched base pairs.

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Excision Repair

Damaged nucleotides are removed from the DNA, a section is replaced with new DNA using the undamaged strand as a template.

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Recombinational Repair

This repair mechanism is used for double-strand breaks, where both strands of DNA are damaged. It involves exchanging DNA segments from a homologous chromosome to restore the damaged region.

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MLH and PMS Proteins

Proteins involved in MMR in eukaryotes, analogous to the MutL protein in bacteria. They help recruit other enzymes to the site of the mismatch.

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Deamination

A chemical reaction that removes an amino group from a molecule. In DNA, deamination of cytosine results in uracil, which is a non-standard base.

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Translesion Polymerases

Specialized DNA polymerases that can bypass damaged DNA, replicating over lesions even if they are not perfectly matched to the template strand.

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Ames Test

A test that identifies potential mutagens by measuring their ability to cause mutations in bacteria.

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Photoreactivation

This repair mechanism uses light energy to break the covalent bonds linking pyrimidines in a thymine dimer, restoring DNA to its original state.

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Methyltransferase

This enzyme removes a methyl group from methylguanine, restoring the base to its original form. However, the methyltransferase is permanently inactivated after a single repair event.

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Why Thymine Instead of Uracil?

DNA uses thymine instead of uracil because deamination of cytosine produces uracil, which is a standard base in RNA. Thymine is a non-standard base in RNA, thus allowing easier identification of deamination events in DNA.

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NHEJ

A DNA repair pathway that joins broken DNA ends without using a homologous template. It involves multiple proteins, including Ku70, Ku80, DNA-PKcs, Artemis, XRCC4, XLF, and DNA ligase IV.

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Ku70/Ku80 Heterodimer

A protein complex that binds to the broken DNA ends in the NHEJ pathway, initiating the repair process. It recruits other proteins, such as DNA-PKcs, to the site of damage.

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DNA-PKcs

A protein kinase involved in NHEJ that forms a complex with Artemis. It helps activate Artemis by phosphorylation, leading to the processing of broken DNA ends before they can be rejoined.

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Artemis

A protein that acts as both an exonuclease and endonuclease, processing and preparing broken DNA ends for ligation in the NHEJ pathway.

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Ligase IV, XRCC4, XLF

Proteins that work together to perform the final step of NHEJ: ligating the processed DNA ends back together, restoring the integrity of the DNA molecule.

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Translesion Synthesis

A DNA damage tolerance mechanism that allows replication to proceed across a lesion, even if the lesion is not fully repaired. It involves specialized DNA polymerases that can synthesize DNA directly across the damaged site.

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Y Family DNA polymerases

Special DNA polymerases involved in translesion synthesis. They can bypass the damaged site and introduce nucleotides, but this process can be error-prone.

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SOS Response

A cellular response to DNA damage that induces the expression of translesion DNA polymerases, allowing replication to proceed across lesions but increasing the risk of mutations.

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Study Notes

Chapter 10: The Mutability and Repair of DNA

  • DNA mutability and repair are crucial for maintaining genetic material across generations
  • Mutations at protein-coding sequences or mRNA expression control regions alter cell phenotypes
  • Changes in DNA sequences play a vital role in evolutionary processes, including the emergence of new species like humans
  • Biodiversity relies on a balance between mutation and repair
  • Key sources of mutations include inaccuracies during DNA replication, chemical damages, and insertion of DNA elements (transposons)

Errors in DNA Replication and DNA Damage

  • Replication errors and DNA damage result in permanent changes to DNA (mutations) and can prevent replication or transcription
  • Key questions addressed in this chapter include how the cells detect mutations, how they are repaired, how cells distinguish parental and daughter strands, and how cells restore proper DNA sequences when original ones are damaged

Replication Errors and Their Repair

  • The Nature of Mutations:

    • Simple mutations include transitions (pyrimidine to pyrimidine, purine to purine) and transversions (pyrimidine to purine, purine to pyrimidine)
    • Point mutations involve insertions or deletions of a single nucleotide

  • Spontaneous Mutation Rate:

    • Mutations arise at a frequency of 10-6 to 10-11 per round of DNA replication.
    • "Hot spots" are regions where mutations arise frequently, including microsatellites.
      • Microsatellites are regions containing di-, tri-, or tetranucleotide repeats
      • CA repeats are found throughout eukaryotic genomes
    • Variations in these regions can affect the number of copies and can be used as markers for inherited mutations

  • Errors escaping proofreading:

    • DNA replication machinery has a proofreading mechanism (3' to 5' exonuclease activity) but some errors still occur
    • These errors lead to permanent changes in the DNA sequence.
    • Mismatch repair is a system to correct mistakes that escape the proofreading mechanism

Mismatch Repair

  • The mismatch repair system enhances DNA synthesis accuracy.
  • Two key challenges for mismatch repair are rapidly scanning the genome for mismatches and accurately correcting the mismatch (specifically, the newly synthesized strand).
  • In E. coli, MutS dimer recognizes mismatches (distorting the DNA structure)
  • Induces a conformational change in MutS, recruiting MutL for the repair system
  • MutL activates MutH to create an incision or nick in the unmethylated strand
  • Exonucleases are used to remove the mismatched DNA segment. Methylation patterns are crucial
  • In eukaryotes, similar mechanisms occur but MutH and Dam methylases are absent
  • Additional proteins like MSH, MLH, and PMS are vital in the eukaryotic system.

DNA Damage

  • DNA damage arises spontaneously from hydrolysis and deamination
  • Mutations result from replication errors or DNA damage
  • DNA damage occurs due to environmental factors (radiation) and chemical agents (mutagens)
  • Examples of deamination are cytosine to uracil, adenine to hypoxanthine, and guanine to xanthine. The presence of uracil in DNA is not normal and can be dangerous
  • DNA can be damaged by alkylation, oxidation, and radiation, which may include UV radiation, which leads to thymine dimer formation, and ionizing radiation

Repair and Tolerance of DNA Damage

  • DNA damage compromises cell viability
  • This chapter details how cells cope with various DNA damage types
  • Excision repair, recombination repair, translesion synthesis are crucial components of the cell's defense mechanism against DNA damage

Other Repair Systems

  • Base Excision Repair (BER): Damaged bases are removed and replaced with correct nucleotides.
  • Nucleotide Excision Repair (NER): Damaged sections of DNA are removed and replaced with functional nucleotides.
    • Critical in repairing thymine dimers and bulky adducts
  • Transcription-Coupled Repair: RNA polymerase identifies sites of damage and recruits DNA repair enzymes.
  • Other DNA Repair Systems: DNA breaks are repaired through recombination-based systems and by processes known as homologous end joining
  • Non-homologous end joining is a critical pathway that uses specialized enzymes to repair double-strand breaks and restore the DNA sequence, though this process can lead to mutations

Translesion DNA Synthesis

  • One mechanism for DNA damage tolerance that bypasses the damaged site.
  • Involves specialized DNA polymerases, such as DNA poly IV or V in E. coli.
  • The incorporation of a correct nucleotide depends on the fidelity of the polymerase involved
  • Human DNA polymerase η inserts two A nucleotides opposite a thymine dimer.
  • Translesion synthesis is mutagenic, often leading to errors that need additional repair mechanisms. Regulation of translesion synthesis is crucial.

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Chapter 10: The Mutability and Repair of DNA PDF

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Explore the critical concepts of DNA mutability and the mechanisms involved in DNA repair. This chapter delves into the implications of mutations on genetic material, evolutionary processes, and biodiversity. Understand how errors in DNA replication and damage influence genome stability and the strategies cells use to rectify these issues.

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