WALLBERG

THEORY OF CANCER • Non-Coding Regulatory RNA

• Warburg Effect aka Aerobic Glycolysis o Micro-RNA (miRNA) & Silencing RNA (siRNA) inhibit Gene Expression
o Long Non-Coding Regulatory RNA (lncRNA)
• Mitochondrial insult à insufficient Cellular Respiration à Tumorigenesis

• Cancer Cells exhibit Glucose Fermentation even when enough Oxygen is present to properly respire
(Glycolysis with Lactate secretion & Mitochondrial Respiration) MUTATIONS
• Permanent heritable DNA mRNA Base & AA Sequence changes
ADENOMATOUS POLYPOSIS COLI (APC) GENE • Point Mutations
o Transition – Purine à Purine/Pyrimidine à Pyrimidine
• Antagonizes WNT-b signaling à stimulating enhanced stimulating growth
o Transversion – Purine à Pyrimidine/Pyrimidine à Purine
• Negative regulator controlling b-Catenin concentrations
o Silent Mutation – New Codon, Same AA (No effect)
o b-Catenin – CHON in Adherent Junctions (Epithelial Tissue integrity)
o Missense Mutation – New Codon, Different AA (Variable effects)
• Interacts with E-Cadherin
o Non-Sense Mutation – New Codon is a STOP Codon (Shorter, Non-Functional)
• Mutations à Adenoma formation à Colorectal Cancer
• Frameshift Mutations – Base Deletion/Addition that should NOT be multiples of 3 (Shorter, Non-
• KRAS – Tyrosine Kinase Signaling Functional CHON)
• BAX – induces Cell Death (Apoptosis) • Large Segment Deletion – large Chromosomal Area loss during unequal Meiotic Crossover (Loss of
Function, Shorter/Entirely Missing)
XENOBIOTICS • Splice Donor/Acceptor – Slice Site loss à AA Addition/Deletion or Exon Deletion (e.g. Tay Sachs
• Phase I – Hydroxylation Reactions catalyzed by Cytochrome P450 Species Disease, Gaucher Disease, b-Thalassemia)
• Phase II – Conjugation Reactions catalyzed by various Enzymes • Triple Repeat Expansion – Coding Region Expansions cause longer & unstable CHON; shows Pedigree
o Glucuronidation (most frequent conjugated reaction) similar to Bilirubin using UDP- Anticipation (e.g. Huntington Disease, Fragile X Syndrome, Myotonic Dystrophy)
Glucuronic Acid catalyzed by Glucuronyl Transferases
SICKLE CELL ANEMIA
NUCLEOTIDES • HbS Point (Missense) Mutation
• Nucleic Acid Building Blocks • b-Chain AA replacement (Glutamic Acid substituted with Valine)
• Purine/Pyrimidine Base + Ribose/Deoxyribose Sugar = NucleoSIDE • Extravascular & Intravascular Hemolysis
o D-Ribose/2-Deoxy-D-Ribose linked to N-1 (Pyrimidine)/N-9 (Purine) by b-N-Glycosidic Bonds • ¯ O2, High Altitudes, Acidosis precipitate Sickling (Deoxygenated HbS Polymerizes) à Anemia
o Purine Nucleosides: Adenosine, Guanosine • Sickle Cell Trait have resistance to Malaria
o Pyrimidine Nucleosides: Thymidine, Uridine, Cytidine • Crescent-Shaped RBCs
• Nucleoside + Phosphate = NucleoTIDE • Skull X-Ray: Crew Cut Sign (­ Erythropoiesis à Marrow Expansion)
o Phosphoryl Group (5’-Phosphate) attached to Pentose C5 by Phosphodiester Bonds • Newborns initially Asymtpomatic (­ HbF, ¯ HbS)
o Purine Nucleotides: Adenine, Guanine • Complications:
o Pyrimidine Nucleotides: Tymine, Uracil, Cytosine o Aplastic Crisis 2° to Parvovirus B19
o Autosplenectomy (Howell Jolly Bodies à ­ Risk of infection from Encapsulated Organisms)
PURINE SYNTHESIS o Splenic Infarct/Sequestration Crisis
1 Ribose-5-P à Phosphoribosyl Pyrophosphate PRPP Synthase ATP o Salmonella Osteomyelitis
2 5-Phospho-b-o-Ribosylamine PRPP Glutamyl Amidotransferase -- o Painful Crises (Vasculo-Occlusive): Dactylitis, Priapism, Acute Chest Syndrome, Avascular
+ Glutamine Necrosis, Stroke
3 Glycinamide Ribosyl-5-Phosphate + Glycine -- o Renal Papullary Necrosis & Microhematuria
4 Formylglycinamide Ribosyl-5-Phosphate Formyltransferase + N10- -- • Treatment: Hydroxyurea (­ HbF), Hydration
Formyltetrahydrofolate
5 Formylflycinamidine Ribosyl-5-Phosphate VI Synthetase --
6 Aminoimidazole Ribosyl 5-Phosphate VII Synthase ATP
7 Amimnoimidazole Carboxylate Ribosyl-5-P VII Carboxylase + CO2 --
8 Aminoimidazole Succinyl Carboxamide IX Synthase + Aspartate --
Ribosyl-5-Phosphate
9 Aminoimidazole Carboxamide Ribosyl-5-P Adenylosuccinase + Fumarate --
10 Formimidoimidazole Carboxamide Ribosyl-5-P Formyltransferase + N10- --
Formyltetrahydrofolate
11 Inosine Monophosphate (IMP) IMP Cyclohydrolase --
12 Adenylosuccinate Adenylosuccinate --
Xanthosine Monophosphate IMP Dehydrogenase --
13 Adenosine Monophosphate Adenylsuccinase --
Guanosine Monophosphate Transaminidase + Glutamine --

PYRIMIDINE SYNTHESIS
1 NH4 + CO2 à Carbamoyl Phosphate Carbamoyl-P Synthase 2 + --
Aspartic Acid
2 Carbamoyl Aspartic Acid Aspartate Transcarbamoylase --
3 Dihydroorotic Acid Dihydroorotase --
4 Orotic Acid Dihydroorotate Dehydrogenase --
5 OMP Orotate Phosphoribosyltransferase --
6 UMP Orotidylic Acid Decarboxylase --
7 UDP ATP --
8 UTP à CTP ATP à CTP Synthase --
dUDP à TMP NADPH à Thymidylate Synthase --

DNA REPLICATION
• Occurs during S Phase
• DNA à DNA (Each Strand serves as a template for Complementary Daughter Strand)

1 Origin of Replication (ori) recognized by Origin Recognition Complex (ORC; DNA-A in E. Coli)
2 Helicase unwinds Double Helix (ATP)
3 ssDNA-Binding Proteins maintain Parent Strand Separation
Topoisomerase relieve Torsal Strain of Helicase-induced unwinding
4 • Type 1: Swivelase
• Type 2: Gyrase à Fluoroquinolones
5 Primase synthesizes short Complementary RNA Primer segments
DNA Polymerase III elongates DNA Strand (adds new Deoxyribonucleotides
6 • Lagging Strand (5’ à 3’ Direction) synthesized continuously & consists of Okazaki Fragments
• Proofreading: Mismatched Nucleotides removed via 3’ à 5’ Exonuclease
7 Another Primer reached à DNA Polymerase I removes Ribonucleotides by 5’ à 3’ Exonuclease
8 DNA Polymerase I fills gap with Deoxyribonucleotides
9 DNA Ligase seals nick (catalyzes formation of last Phosphodiester Bond; ATP)

TYPES OF RNA
• Messenger RNA (mRNA) – carries Genetic Information from Nuclear DNA to Cytosol
o CHON Synthesis Template
o 5’ End: Methylguanosine Cap (prevents Digestion)
o 3’ End: Poly (A) Tail
o undergoes Modification in Eukaryotic Cells
• Ribosomal RNA (rRNA) – MOST NUMEROUS (Rampant), Ribosome formation (CHON Synthesis site)
• Transfer RNA (tRNA) – SMALLEST (Tiny), translate mRNA Nucleotide Sequences into specific AAs
• Small Nuclear RNA (snRNA) – rRNA & mRNA Processing & Gene Regulation