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Questions and Answers
What is the role of histone modification in DNA packaging?
Which of the following correctly describes the structure of DNA?
In DNA replication, which enzyme is responsible for synthesizing the leading strand?
Which statement accurately describes how nucleotides are bonded in the DNA structure?
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What distinguishes the lagging strand from the leading strand during DNA replication?
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Which of the following bases pairs with two hydrogen bonds in DNA?
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Which of the following enzymes is specifically involved in creating RNA primers during DNA replication?
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Which statement accurately reflects Chargaff's rule?
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What is the primary role of M6P in lysosomal protein sorting?
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What is the main characteristic of Niemann-Pick C Disease?
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Which of the following correctly describes a catabolic pathway?
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What type of reaction is favored according to thermodynamics in biochemistry?
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How are NADH and FADH2 involved in ATP synthesis?
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Which of the following statements about lysosome enzyme delivery is true?
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Which of the following is NOT a benefit of glycosylation in proteins?
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What is a significant consequence of the decreased LDL receptor synthesis in Niemann-Pick C Disease?
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Which metabolic process primarily occurs in the liver to maintain blood glucose levels?
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Which statement best describes the TCA cycle's role in metabolism?
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What role does DNA ligase play during DNA replication?
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Which mutation type involves the substitution of a purine for a pyrimidine?
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Which process modifies pre-mRNA by removing introns and joining exons?
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What does the 5' cap and poly-A tail on mRNA achieve?
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Which of the following is a common characteristic of prokaryotic transcription?
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What is the primary function of the RNA polymerase during transcription?
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Which type of RNA is responsible for carrying amino acids to the ribosome during translation?
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What is the function of the Polycomb Repressive Complex 2 (PRC2) in gene expression?
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Which DNA repair mechanism can fix double-strand breaks?
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In eukaryotic cells, where is DNA primarily located?
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What type of chromatin is transcriptionally active and accessible to transcription factors?
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Which type of mutation does not get passed to offspring?
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What happens during the elongation phase of transcription?
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What are stop codons responsible for during protein synthesis?
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Study Notes
DNA Replication
- DNA ligase joins Okazaki fragments to the growing strand
- DNA gyrase prevents supercoiling of proximal DNA strand
- Replication is semi-conservative; with strands running anti-parallel
Genome Variability
- Germline mutations are DNA changes that are passed on
- Somatic mutations are DNA chagnes that are not passed on
- Inversion: DNA segment is flipped
- Deletion: DNA segment is removed
- Translocation: DNA segment moves to a different chromosome
- Transition: purine is switched for a purine or a pyrimidine is switched for a pyrimidine
- Transversion: purine is switched for a pyrimidine
- Duplication: DNA segment is copied
- Mutation: uncommon alteration in DNA sequence
- SNP: common inherited change in a single base pair that occurs in at least 1% of the population
- Example: p53
- Stabilizes to stop cell division to repair DNA
- If DNA can't be repaired, then DNA is degraded
- Tumor suppressor
- SNP increases cancer susceptibility
DNA Damage and Repair
- DNA damage can be caused by replication stress, oxygen radicals, ionizing radiation, UV light, and polycyclic aromatic hydrocarbons
- Common types of damage include base mismatches, single-strand breaks, double-strand breaks, and bulky adducts/intrastrand crosslinks
- Repair mechanisms include mismatch excision repair, base excision repair, homologous recombination & non-homologous end-joining, and nucleotide excision repair
Mitochondrial DNA
- Maternally inherited
Gene Expression
- Genome size doesn't determine complexity
- Sophistication of gene expression helps us adapt to stimuli
- Brings risk associated with responding to mutations
RNA
- 2' hydroxyl on sugar; Uracil replaces Thymine
- Classifications
- RNA
- Messenger RNA
- Non-coding RNA
- Housekeeping ncRNA
- tRNA
- rRNA
- Regulatory ncRNA
- Long non-coding RNA
- Small non-coding RNA
- Micro RNA
- Small nuclear RNA
- PIWI interacting RNA
- Housekeeping ncRNA
- RNA
Location
- DNA: nucleus and mitochondria
- RNA: cytoplasm
Protein-Coding Gene
- Regulatory sequence controls when and where expression happens in protein-coding region
- Promoter and enhancer regulate transcription into pre-mRNA, which is then modified
- mRNA 5' and 3' untranslated regions regulate transcription
Transcription
- Initiation, Elongation, Termination
- RNA polymerase binds promoter; promoter itself isn't transcribed
- Initiation of RNA synthesis by binding NTP to antisense strand of DNA, moving 5' to 3'
- NTP loses 2 phosphates to generate energy (ATP)
- Elongates until termination signal
- Pre-mRNA detaches from the template strand and DNA rewinds; RNA polymerase detaches from the DNA
Post-Transcriptional Modification
- 5' cap prevents degradation and helps binding
- Removal of introns and exons joining by differential splicing spliceosome:
- Catalyzed by small nuclear ribonucleoproteins (snRNPs) of the spliceosome
- Spliceosome recognizes splicing signals to bring introns together
- Have GU at 5' end and AG at 3' end
- Branching point within the intron has Adenosine
- Splice out as a lariat structure
- Poly-A tail enables export to cytoplasm and prevents degradation
Prokaryotes
- Single transcript
- One step, fast
- Cytoplasm
- Single RNA polymerase synthesises all the 3 types of RNA
- Several co-regulated genes (operon)
- Corresponds directly to protein sequence (no introns)
Thalassemia
- Mutation G to A in exon-intron junction
- snRNP doesn't recognize junction
Systemic Lupus Erythematosus
- Body produces antibodies against snRNPS
- Defective splicing
Translation
- Ribosome:
- A Aminoacyl site
- P peptidyl transfer site
- E exit site
- P and A site has transfer of charges to cause PP binding
- Stop codons:
- UAG, UAA, UGA
Post-Transcriptional Modifications
- Phosphorylation
- Methylation in CG-rich promoter regions inhibits transcription
- Polycomb Repressive Complex 2 (PRC2) using SAM to close chromatin and prevent RNAPII binding
- Acetylation Histone acetyltransferases (HATs) with acetyl-CoA
- Chromatin opens to allow RNAPII to bind to promoter and induce expression
Euchromatin
- Transcriptionally able; loose and accessible by transcription factors
Heterochromatin
- No transcription; tight and inaccessible by TF
Proteins and Enzymes
Lysosomal Hydrolase Precursor
- Enters golgi from ER
- Phosphate is added, forming M6P
- Sorting signal
- Sugar added for solubility (glycosylation)
- M6P binds M6Pr in golgi to prelysosomal endosome
- Receptor-dependent transport of vesicle from prelysosomal endosome
- Endosome is acidified by H+ pump
- M6P dissociates
- M6Pr localize within budding vesicle
- Receptors are recycled back to trans golgi
- Some leak outside of the cell to the PM, helpful with disease treatment
Niemann-Pick C Disease
- Affects children at school age; rapid neurological impairment
- Death in teen years
- NS mutation: Gly992Tyr
- Affects the cell's ability to deliver cholesterol from NPC1
Mechanism of Action of NPC1
- NPC1 delivers cholesterol to NPC2 on the golgi
- Cells take up cholesterol by LDL endocytosis
- Increased unesterified cholesterol
- Decreased LDL receptor synthesis, less intake
- Decreased cholesterol synthesis, less production
- Decreased esterification and storage, less storage and modification
Therapies
- Miglustat: decreases glycolipid synthesis; reduces lysosomal congestion
- Cyclodextrins: synthetic cholesterol carriers; facilitate transport
- Histone deacetylation inhibitors (HDACi): blocks the inhibition of transcription; increases transcription of functional NPC1
Fabry Disease
- Deficient alpha-galactosidase enzyme
- Unable to degrade glycosphingolipids
Therapy
- Enzyme replacement therapy
- After M6P and M6Pr are recycled there can be mistargeting
- Healthy alpha-galactosidase is taken up with M6Pr and can allow some processing
- Very expensive and unethical
Introduction to Metabolic Biochemistry
- Catabolic pathway:
- Breakdown biomolecules to get complex macromolecules, ATP, and/or electron donors (NADH, FADH2)
- Anabolic pathway
- Use ATP and reduced co-factors to make complex macromolecules
- Catabolic and Anabolic pathways must differ by at least one step, to not be a futile cycle
Thermodynamics and Free Energy
- [Energy intake equals energy expenditure plus weight gain or loss]
- Exergonic reactions are favoured
- Final product loses free energy and has negative delta G
- Endergonic reactions are unfavourable
- Product has a positive delta G
- Can be made to proceed if coupled to a exergonic reaction
Redox Reactions and ATP Synthesis
- Oxidoreductase enzymes transfer electrons to coenzymes NAD+ or FAD, reducing them to form NADH and FADH2
- NADH and FADH2 are re-oxidized to NAD+ and FAD in the ETC, coupled to ATP synthesis by oxidative phosphorylation
Glycogen
- Branched polymer of glucose
- Glycogen to glucose= glycogenolysis
- Glucose to glycogen= glycogenesis
- Two most important storage organs
- Liver: control of blood glucose level
- Skeletal muscle: for its own energy needs
Glycolysis
- Catabolic pathway converting one molecule of glucose to two molecules of pyruvate in the cytosol
- Glucose + 2 ADP + 2 NAD+ 2 Pyruvate + 2 ATP + 2 NADH
- Requires molecular oxygen
- In anaerobic conditions, forms lactate through the Cori cycle
TCA Cycle
- Catabolism of carbs, AA, and FAs converge (mitochondria)
- Carbon enters as Acetyl-CoA
- Key intermediate and allosteric regulator of many enzymes
- Provides maximum energy: up to 32 ATP per glucose oxidized
Gluconeogenesis
- Used mainly by liver to replenish BGL
- Uses precursors like pyruvate, lactate, glycerol, and some AA
- Cannot use Acetyl-CoA
Signal Transduction and Cell Fate
General Principles
- Cell-surface receptors
- Hydrophilic signal molecule binds surface receptor on the PM
- Activates second messenger system to cause change in DNA that leads to an effect
- Intracellular receptors
- Carrier protein brings small hydrophobic signal molecule to the cell
- Crosses through membrane and interacts with intracellular receptor in the nucleus to effect change
Classification of Extracellular Signals
- Classified chemically, by nature of transmission, or by system
- Signal molecules are polar and need membrane receptors, or non-polar and can cross PM
- Contact-dependent signal and receptor bound to membrane
- Paracrine are released and have effect close by
- Synaptic: Neuro
- Endocrine released to have effect far away
Important Themes in Signal Transduction
- Foundations: Biochemistry Summary Sheet
Genome
DNA Packaging
- DNA double helix wrapped around histones
- Histones (basic) have a positive charge that binds to the negative phosphate group (acidic) of DNA
- Histone modification helps regulate DNA packing and gene expression (epigenetics)
- Tightly wrapped= decreased gene expression; needs to be loosened to interact with transcription factors
- 4 histone types:
- H2A, H2B, H3, and H4
- DNA wrapped around 8 histones= nucleosome
- Nucleosomes wrapped tightly into a helical fiber
- Helical fiber wraps into supercoil
DNA Structure
- Consists of 2 strands of nucleotide polymers
- Nucleotide consists of a base, sugar, and phosphodiester linkage
- Four bases:
- Adenosine and Guanine= purines
- Thymine and Cytosine= pyrimidines
- A and T pair with 2 hydrogen bonds
- C and G pair with 3 hydrogen bonds
- Chargaff's rule: number of A=T and C=G in nuclear genome; not the case for mitochondrial genome or in prokaryotes
- Nucleoside Purine/pyrimidine base attached to the deoxyribose sugar
- Nucleotide: Purine/pyrimidine base attached to deoxyribose sugar, with the phosphate attached
- Stabilized by:
- Base stacking
- Hydrophobic interactions
- Van der Waals forces
DNA Replication
- Helicase unwinds the parental double helix
- Single-stranded binding proteins stabilize the unwound parental DNA
- Leading strand is synthesized continuously in the 5' to 3' direction by DNA polymerase
- Goes towards the replication fork
- DNA polymerase has polymerizing and proof-reading activity (3' to 5' exonuclease activity)
- Lagging strand is synthesized discontinuously
- Primase synthesizes a short RNA primer
- Primer is extended by DNA polymerase to form Okazaki fragments
- Goes away from the replication fork
- RNA primer is replaced by another DNA polymerase
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Description
Test your knowledge on DNA replication mechanisms and the concepts of genome variability. This quiz covers essential terms and processes, including mutations and their implications for genetic diversity. Assess your understanding of key enzymes and the significance of different mutation types.
