From DNA to Protein: Gene Expression and Mutation

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Gene Expression: From DNA to Protein

Genes Code for Proteins

Genes are segments of DNA that encode instructions for the synthesis of proteins, which carry out most cellular functions. Early studies of genetic diseases, such as alkaptonuria and phenylketonuria (PKU), revealed that mutations in specific genes lead to the accumulation of toxic metabolic products due to nonfunctional enzymes.

Alkaptonuria: Caused by a mutation that prevents the breakdown of homogentisic acid, leading to its accumulation and darkened urine.
One-gene, one-enzyme hypothesis: Each gene encodes a single enzyme; later revised to one-gene, one-polypeptide, as many proteins are composed of multiple polypeptides.
Model organisms: Used in genetic studies due to ease of manipulation and rapid growth (e.g., Neurospora crassa).

Alkaptonuria and Phenylketonuria metabolic pathway One gene, one enzyme experiment with Neurospora

Information Flows from Genes to Proteins

Gene expression involves two main steps: transcription and translation. The central dogma of molecular biology describes the flow of genetic information from DNA to RNA to protein.

Transcription: DNA is copied into RNA.
Translation: RNA is used as a template to synthesize proteins.
RNA types: mRNA (messenger), rRNA (ribosomal), tRNA (transfer).
Viruses: Some use RNA as genetic material; retroviruses use reverse transcription to integrate into host genomes.

Central dogma of molecular biology From gene to protein: transcription and translation

DNA Is Transcribed to Produce RNA

Transcription is the process by which RNA polymerase synthesizes RNA from a DNA template. The RNA produced is complementary to the template strand and similar to the coding strand.

Requirements: DNA template, ribonucleoside triphosphates (ATP, GTP, CTP, UTP), RNA polymerase.
Steps: Initiation (RNA polymerase binds promoter), Elongation (RNA synthesis), Termination (RNA detaches).
RNA polymerase: Adds nucleotides in 5′-to-3′ direction; does not require primers.

RNA polymerase interacting with DNA DNA transcription steps

Eukaryotic Pre-mRNA Transcripts Are Processed prior to Translation

In eukaryotes, pre-mRNA undergoes several processing steps before translation. These include addition of a 5′ cap, a poly-A tail, and removal of introns via splicing.

Nucleic acid hybridization: Reveals introns (noncoding regions) in eukaryotic genes.
Splicing: Introns are removed, exons are joined to form mature mRNA.
5′ cap: Modified GTP added for ribosome binding and protection.
Poly-A tail: Added for stability and export from nucleus.

Nucleic acid hybridization and introns Transcription of a eukaryotic gene Processing the ends of eukaryotic pre-mRNA RNA splicing

The Genetic Code Determines the Protein Sequence Encoded by an mRNA

The genetic code is a set of rules by which the sequence of bases in mRNA is translated into the sequence of amino acids in a protein. Each codon (three-base sequence) specifies a particular amino acid.

Start codon: AUG (methionine).
Stop codons: UAA, UAG, UGA (signal termination).
Redundancy: Most amino acids are specified by more than one codon.
Universality: The code is nearly universal across all organisms.

Deciphering the genetic code experiment The genetic code table

Translation: mRNA to Protein

The Coding Sequence in mRNA Is Translated into Proteins by Ribosomes

Translation is the process by which ribosomes synthesize polypeptides using mRNA as a template. tRNA molecules bring specific amino acids to the ribosome, matching codons with their anticodons.

tRNA: Binds amino acids, matches anticodon to mRNA codon, interacts with ribosome.
Charging: Aminoacyl-tRNA synthetases attach amino acids to tRNA using ATP.
Ribosome structure: Large and small subunits; three binding sites (A, P, E).
Translation steps: Initiation (assembly of complex), Elongation (peptide bond formation), Termination (release of polypeptide).
Polysomes: Multiple ribosomes translate a single mRNA simultaneously.

Transfer RNA structure Charging a tRNA molecule Ribosome structure Initiation of translation Elongation of translation Termination of translation Polysome structure

Polypeptide Modification and Transport

Polypeptides Can Be Modified and Transported during or after Translation

After translation, polypeptides may undergo modifications and be transported to specific cellular locations. Signal sequences direct proteins to their destinations, and posttranslational modifications alter protein function.

Signal sequences: Direct proteins to organelles (e.g., nucleus, ER).
Posttranslational modifications: Proteolysis (cutting), glycosylation (adding sugars), phosphorylation (adding phosphate groups).
Protein targeting: Proteins may remain in cytosol or be transported to organelles or secreted.

Testing the signal sequence experiment Destinations for newly translated polypeptides in a eukaryotic cell

Gene Mutation and Molecular Medicine

Mutations Are Heritable Changes in DNA

Mutations are changes in the DNA sequence that can be inherited by cells or organisms. They can occur in somatic or germ line cells and have various effects on protein function.

Types: Loss of function (recessive), gain of function (dominant), conditional, reversion.
Point mutations: Substitution, insertion, or deletion of a single base pair.
Chromosomal rearrangements: Deletion, duplication, inversion, translocation.
Mutagenesis: Spontaneous (errors, tautomers) or induced (chemical, radiation).
Transposons: Mobile genetic elements that can cause mutations.

Mutation and protein function Two types of base pair substitutions Mutations: silent, missense, nonsense Sickle and normal red blood cell Chromosomal rearrangements Spontaneous mutations Spontaneous mutations (part 2) 5-methylcytosine in DNA is a hot spot for mutations

Summary Table: Types of Mutations

Type	Description	Effect
Point Mutation	Single base substitution, insertion, or deletion	Silent, missense, nonsense, frameshift
Chromosomal Rearrangement	Large-scale changes (deletion, duplication, inversion, translocation)	Gene disruption, dosage effects
Transposon Insertion	Mobile element inserts into gene	Loss of function, gene duplication
Spontaneous Mutation	Errors during replication or repair	Random, often neutral or deleterious
Induced Mutation	Caused by mutagens (chemicals, radiation)	Varied, often deleterious

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