DNA Damage and Mutations-021

Overview

Process of Gene Expression:

  • In transcription, the information in the DNA is used to create a molecule of RNA

  • In translation, that RNA is used to produce a protein that can be carried out the functions of the cells

Mutation

  • Heritable change to the DNA

  • Once the mutation occurs, it is passed down to daughter cells

  • Spontaneous and random

  • Point mutation: one or a few nucleotides affected

  • Mutations may be beneficial, harmful, or neutral

Errors or damage become mutations after replication has occurred

  • Replication error: DNA polymerase makes a mistake in replication of DNA

  • DNA Damage: caused by spontaneous reactions or exposed by mutagens

  • Damage or errors are not mutations! They become mutations after replication

Summary

  • Mutations are heritable changes in the DNA

    • Errors or DNA damage that has been replicated

  • Most mutations are spontaneous and random

  • Mutations may be beneficial, harmful, or nuetral

  • Mutations are key drivers of change!

Repair of Replication Errors

Errors during the replication process are often detected by DNA polymerase

  • DNA replication occurs in the S phase

  • Proofreading: when the DNA polymerase is actively working and it catches an error

  • How does DNA polymerse sense this error

    • Due to DNA Polymerase is very accurate it is able to detect that error

Errors just after the replication process

  • S phase or G2 of the cell cycle

  • DNA polymerase has already moved on from this part of the genome

  • How does the cell sense this error?

    • There are chemical difference between the parent strand that was used as the template in replication between the parent strand and the newly synthesized daughter strand, and the cell can detect what is new and what is old

  • How strand likely contains the error?

    • The daughter strand

Every time a cell replicates its genome, there is an opportunity for mutations to occur

  • The overall mutation rate in humans is very low per each round of replication

  • What about viruses?

    • RNA viruses have a higher mutation rate than DNA viruses

Summary

  • Mutations can be cause by replication errors

    • Less than 1 error per 10 billion nucleotides replicated in humans

  • Erros are rate due to

    • high accuracy of DNA polymerase

    • DNA polymerase proofreading

    • Error detection and repair just after replication

  • Before replication errors can lead to mutations, cells that divide more are more likely to have mutations

  • DNA polymerase can synthesize and proofread a DNA sequence

Detection and Repair of DNA Damage

DNA can be damaged by spontaneous events

  • Spontaneous DNA damage can occur at any time in the life of a cell

  • Reactive oxygen species

Various environmental exposers can be mutagenes

  • UV rays

    • Cross-linked thymine bases

  • Tobacco smoke

    • Bulky side group attached to a base

  • X-rays

    • Double-stranded break in DNA backbone

  • Some chemicals cause insertion or deletions of nucleotides

General strategy for correction of error or damage

  • Recognize damage

  • Fix damage

    • Remove damage(specialized enzymes)

    • Use undamaged strand as template for repair(DNA polymerase)

      • Or Join broken strands(DNA Ligase)

  • Repairs occur throughout the cell cycle

  • Deamination:is the removal of an amino group

Summary

  • Spontaneous DNA damage is common in cells

  • Damage can also be cause by mutagens (UV light, X-rays, chemicals)

  • Many different DNA repair processes are constantly working to detect and accurately repair DNA damage

  • Overall, mutations in human cells are quite rare

Small and large-scale mutations

Point mutations arise from errors in replication and DNA damage that alter the DNA

Point mutations in protein-coding regions

Point Mutations in protein-coding regions classified by effect on the amino acid sequence

  • Substitution mutation: change one base pair to another

    • Synonymous mutations: Does not change the amino acid

      • Most amino acids are coded for by more than one codon

      • Does not change the protein structure

    • Missense mutation: changes an amino acid

      • This may affect the protein structure if the mutation results in an amino acid with different properties

    • Nonsense mutation: creates a stop codon

      • May shorten the protein

  • Insertion/deletion mutation: add or delete one or more base pairs

    • Frameshift: Insertion that changes the reading frame in translation

      • Anything other than a multiple of 3 base pairs

      • Changes many amino acids after the site of the mutation

    • Indel without frameshift: insertion that does not change the reading frame in translation

      • Multiple of 3 base pairs

      • Adds or deletes one amino acid

Large-scale Scale Chromosomal mutations arise from double-strand breaks

  • Double-stranded break in the DNA backbone

Double-strand breaks can lead to information loss

  • A reciprocal translocation is a type of large chromosomal damage

Summary

  • Mutations can be point mutations(single base-pair changes & small insertions/deletions) or large-scale changes(chromosomal mutations)

  • Point mutations in protein-coding sequences, including synonymous, missense, nonsense, and frameshift mutations

    • Of these, nonsense and frameshift mutations have the greatest effect on protein structure

    • All mutation that alter amino acids have the potential to alter protein function