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Chromatin structure, and charge on DNA/Histones

Chromatin: DNA + histone proteins wrapped in a tightly compacted situation
-DNA is negative; histones are positive

Mitochondrial genome has ... (3)

-circular molecules
-multiple different copies
-encodes 13 proteins

Euchromatin vs Heterochromatin

Euchromatin: light stain, loose DNA, allows xC

Heterochromatin: tight DNA, dark stain

Active Transport into nucleus

Importin binds molecule
-taken into nucleus, importin comes off
-importin binds ranGTP, taken back into cytosol
-Ran-GAP cleaves complex; importin stays in cytosol

Active Transport out of nucleus

Exportin binds mRNA; binds RanGTP as well
-complex exported to cytoplasm
-Ran-GAP cleaves complex


on 3' end of DNA; prevents digestion by enzymes

-Telomerase add to telomeres

GGGTTA repeats


-different versions of the same gene

Point Mutation

-one base change
-can change AA, or may remain same


Insertion or deletion, can result in frame shift

If adenine get's depurinated ....

then you can get thiamine dimers

End-joining Mutations (2)

non-homologous: resulting from helix breakage and repair

homologous: resulting from sister chromatids acting as template for repair

Triplet Expansion: what is it, and what disease?

-CpG repeats cause incorrect adherence during meiosis


Non-disjunction: what is it, and what disease?

-separation in Anaphase 1 leads to uneven separation of chromosomes


Silent Mutation

-single base change, no AA change

Missense Mutation

-single base change, different AA creates

Non-sense Mutation

-single base change, stop codon (UGA, UAG, UAA) created

Frameshift Mutations

-result from in/dels

Transposon Mutations

randomly insert selves into DNA

Exicision Nuclease (and associated disease)

Repairs DNA double strand breaks
-Xeroderma Pigmentosa


One person can have different genes in different cells;
-during development, certain gene mutations can be acquired at different times ... resulting in different cellular karyotypes in same person

DNA Replication (leading and lagging strand)

1) DNA Helicase opens DNA
*topoisomerase 1 prevents supercoiling
2) Primase adds primer
3) DNApol-alpha starts adding dNTPs
4) DNApol-delta takes over

*leading strand; in the direction of opening; continuous addition
*lagging strand; in opposite direction of opening; discontinous addition; RNAase needed to remove primer; DNApol-delta needed to fill in gaps; ligase needed to ligate fragments

DNA pol delta: special ability?

3' to 5' exonuclease ability


adds to lagging strand on 3' end of DNA
(has RNA component that is uses as guide)

Cytarabine: drug mechanism

Good cancer treatment
-inserts arabinose instead of ribose into cytosine nucleotides
-prevents DNA replication

Cyclophosphamide: drug mechanism

-converted to phosphamide in liver
-ALKYLATES DNA, blocking replication

Doxorubicin: drug mechanism

Cancer treatment
-inhibits topoisomerase 2, so no religation of broken strands occurs

Imelestat: drug mechanism

binds RNA template on telomerase

Lynch Syndrome

-mismatch repair system messed up
-leads to HNPCC

Bloom Syndrome

DNA helicase defect
-Okizaki fragment joining impaired

RNA polymerases (differences from DNA pol)

-no exonuclease activity
-no primer needed
-more errors

Which RNA pols make tRNA, mRNA, and rRNA

3: tRNA

2: mRNA

1: rRNA

Transcription: initiation

1) TF2D binds DNA (helicase unwinds)
2) RNA pol 2 binds, get's p-lated, and rapid xC occurs

Alpha-amanitin poisoning

-inhibits RNApol2

pre-mRNA Processing ... (3 things)

1) 5' methyl-guanosine cap
2) splicing by splicosome
3) 3' poly-A tial

RNA splicing

1) Adenine at branch point cuts 5' splice site
2) Free OH at 5' splice site attacks 3' splice site intron
3) lariat shaped intron made!


-presence of cryptic splice site ... leads to incorrect splicing

Chromatin Remodeling Complexes (HATs vs HDACs)

HAT's; histone acyl transferase; transfer acyl group to lysine, making it less positive; less attraction between DNA and histone ... leads to

HDAC's: histine deacetylases; remove acyl groups from histones

What is the role of DNA binding proteins?

-to recruit HAT's or HDAC's

LDL receptor gene regulation

1) SP-1/CRSP always bound to gene
2) SREBP binds SRE, increases HAT's

*this occurs during low cellular cholesterol conditions
-this is partially how statin drugs work

Hydrophobic hormone binding mechanism

1) diffuse through membrane
2) bind to receptor in cytosol
3) taken to nucleus to bind HRE (hormone receptive elements)

Thyroid Hormone Binding Mechanism

1) T3 binds internal receptor
2) taken to nucleus, T3 binds to THR-RXR; causes removal of HDACs, and addition of HAT's

PKA mediated xC control

1) PKA p-lates CREB
2) CREB-P binds CRE
3) Complex binds CBP in nucleus, and HAT's recruited

Rubenstein-Taybi Syndrome

"The Creb-B jew!"

-Creb-BP mutation


-inhibits estrogen receptor


Ribosome Sizes: EuK, ProK, Mito

EuK: 80S (40 + 60)
Mito: 60S
ProK: 70S (50+30)

Ribosome: Small subunit vs large subunit function

Large Subunit: enzymatic activity

Small Subunit: binds the RNA's

xL: initiation

1)eIF-2A binds GTP; complex then binds tRNA-met (ternary complex)
2) Ternary complex then binds small subunit
3) mRNA binds complex
4) Large subunit binds complex
5) eIF2A hydrolyzed

xL: elongation

1) tRNA-met in P site
2) new tRNA comes in with EF-1-GTP
3) complex moves with help of EF-2-GTP

xL: termination

1) Stop codons binds A-site
2) eRF-GTP binds stop codon, gets hydrolyzed
3) complex falls apart


binds small subunit of ribosome


-mimics tRNA by binding A site


prevents peptidyl-bond formation


removes adenine bases

Diptheria Toxin

Inactivates EF-2

N-linked glycoslyation


1) Dolichol-P adds NAGA x 2
2) Mannoses added
3) Compound flipped into ER
4) Dolichol-P adds glycoslate to protein on Asn residues

N-linked glycoslyation; 2 subtypes

1) High mannose
2) Complex

*these modifications occur in the golgi

O-linked glycosylation

-occurs on H-antigen on RBC

-occurs on proteoglycans of ECM

Lysosomal Protein Localization

-must have mannose-P added
-P-lated protein goes to lysosome

Mitochondrial Protein Localization

Needs TOM/TIM complex to guide it

I-cell disease

Lysosomal proteins appear in cytoplasm because mannose-P mechanism is not working

3 Main checkpoints of cell cycle

1) S-phase checkpoint
2) G2/M checkpoint
3) Metaphase/Anaphase checkpoint

G1-CDK and G1/S-CDK target what protein?


S-CDK targets what gene?



1) GF binds
2) Ras activated
4) Increase in MYC

G1 to S-phase transition: mechanism

1) Mitogen binds
2) Cyclin D produced
3) Rb-E2F get's P-lated: Rb-P falls off, E2F acts as TF
4) Cyclin E and A made; CHECKPOINT PASSED

p53 Mechanism

1) UV damage to DNA
2) P53 p-lated
3) Increases p21 (which inhibts G1/S and S cdk's) and p27 (which inhibits CDK's too)

Role of APCs (anaphase promoting complex)

polyubiquinate s and m cdk's

dephos Rb


targets p53 for proteosome degradation

Apoptosis mechanism

1) BAX promotes apoptosis; creates channel in mito
2) Cytochrome C's escape
3) Apoptosome created
4) Caspaces trigger cell death

Oncogene, Proto-oncogene, TSG's: please define

Oncogene: a gene that has been mutated to a state of increased or constant expression ... helps cell cycle move forward

Proto-oncogene: a gene that can become mutated to become an oncogene

TSG: tumor suppressor gene; a gene that stops the cell cycle in order to prevent inappropriate division

Top 3 Causes of Death

1) Heart Disease

2) Malignant Neoplasms

3) Cerebrovascular Disease

What are two mechanisms by which genes get changed into cancer-promoting agents?

1) DNA sequence gets changed

2) Epigenetic changes, including methylation

6 Abilities Cancer Cells need to acquire ...

1) Ability to grow without mitogens
2) Loss of adherance abilities
3) Apoptosis evading mechanisms
4) Insensitivity to contact inhibition
5) Limitless replication (telomerase activity)
6) Sustained angiogenesis

Example of 2 most famous TSG's



Example of 3 Most famous oncogenes

Myc (TF)

Ras (membrane signalling)

Erb-B2 (her2/neu)

Erb-B2 Mutation

aka her2/neu

-constitutively active tyrosine kinase
-doesn't need EGF to grow

Ras signalling

1) Mitogen (GF) binds cell receptor
2) Ras drops GDP, binds GTP
3) Ras-GTP activates RAF
*shut down occurs when GAP hydrolyses GTP

Myc function (and associated cancer)

TF that promotes xC of CDK's


p53 function (and associated cancer)

1) DNA damage occurs
2) p53 gets p-lated, MDM2 falls off
3) p53 act as TF for p21 and p27

*found in Li-Fraumeni

What does HPV target?

Produced E6 and E7

E6: inhibits p53

E7: inhibits p53, p21, and Rb

FAP cancers (and progression)

-colorectal cancer
-characterized by the presence of thousands of polyps

-Defective APC

1) defective APC inherited
2) second allele lost
3) Ras actvated
4) Loss of DCC, then p53

APC function

-TSG; inhibits B-catenins

*B-catenins increase activity of myc and cyclin D

Lynch Syndrome

-don't have as many polyps

-Loss of mismatch repair genes, and microsatelite instability

Malignant (metastatic) cancers have lost ...

adherance capabilities. Loss of E-cadherins (TSG)

Metastasis: invasion

-use serine proteases to break down collagen

Philadelphia Chromosome: defect, which cancer?

-translocation of ABL from chromosome 9 to chromosome 22; comes under regulation of BCR gene




MAB that binds her2/neu receptors; causes internalization


-targets CD20+ in non-hodgkins lymphoma
-targets cells for destruction

Ras Signaling: Normal and Mutant

Normal: Ras bind GTP; Mapkkk sequence, c-myc activity increased

Mutant: loses GTPase activity

Burkitt's Lymphoma cause

-balanced translocation of myc

Li Fraumeni Syndrome

-Loss of p53 function

Treatments for Rb (3)

1) Vincristine -inhibits microtubule
2) Carboplatin - alklylated DNA
3) Etoptoside - inhibits topo iso 2

FAP inheritance and defect

-on APC gene (TSG);
-autosomal dominant

APC normal function

-inhibits B-catenins
-B-catenins upregulate myc and D-cyclins

FAP progression

1) Inherited FAP
2) 2nd FAP mutation

CML cause

-The philadelphia chromosome
-ABL (oncogene) moves to BCR promoters area

Imantinib Mesylate (Gleevec)

TKI inhibitor: CML

Breast Cancer treatments (3)

1) Herceptin: binds EGF receptor (her2neu)
2) Leptanib: TKI inhibitor
3) Gefitinib: EGF inhibitor


MAB targeting CD20+ cells;
-treatment for non-hodgkin lymphoma; targets cell for destruction


DNA intercolating agent that decreases the activity of topoisomerase II

Naladixic Acid

inhibit bacterial topoisomerase 2


inhibit bacterial topoisomerase 2

Sickle-Cell Disease

-E to V mutation at AA#6; results in abnormal beta chain; sickle cell formation

Triplet Expansion found in what disease?


Non-disjunction found in what disease?

Down's Syndrome

Xeroderma Pigmentosa

-loss of excision endonuclease


-Cancer treatment
-In cytosines, it inserts an arabinose in place of ribose


-converted to phosphamide in liver
-acts as alkylating agent of DNA


-intercolating agent, blocks topoiso2 action


binds RNA template on telomerase

Lynch syndrome defect in ...

mismatch repair

Bloom syndrome defect in ... find what?

DNA helicase; results in increased okisaki fragments

When RNA pol 2 gets P-lated, what happens?

Other TF's fall off (TF2D) and xC goes faster


Poison of the death cap mushroom;
-inhibits RNA pol 2


Inhibits RNA pol 2 in gram + bacteria
-can induce cP450's

What does LDL receptor bind,

-Binds Apo B, E on LDL and VLDL

1) CRSP-SP1 always bound on LDL gene
2) SREBP-SRE bind CRSP-SP1; increase HATs!

Cortisol mechanism

1) Binds receptor inside cell
2) Dimerizes
3) Binds to nucleus, acts as TF

PKA cell signaling

1) CREB gets P
2) Creb-P binds CRE
3) Creb-P-CRE bind to CBP
4) Increased HATs!


Creb Binding Protein defect


-estrogen receptor inhibitor
-still binds nucleus but no XC


binds small subunit of 16s ribosome in bacteria


AB: mistranslation of codons


blocks A-site (mimics tRNA)


prevents peptidyl bond formation


inactivates ribosome; hyrolyzed adenine on rRNA

Diptheria Toxin

Inactivates EF2 by adding ribose to dipthamide

Cystic Fibrosis Defect

-CFTR doesn't get properly glycated

I-cell disease defect

Mannose-P not present, so you don't get localization into lysosome

Ubiquinone amide bond

Creates amide bond between glycine on UBQ and lysine on protein

In N-linked and O-linked glycoslyation, where do sugars add to on proteins?

N-linked: AsN

O-linked; serine/threonine

Top 3 Causes of Death

1) Heart Disease
2) Malignant Neoplasms
3) Cerebrovascular disease

Cancer History

First record of cancer: 1600 BC

Hippocrates: used "carcinomas" for crab, due to the angiogenesis

Galen: used 'oncos' for swelling

Cancer definition

Genetic disease of the somatic cells characterized by uncontrolled cell division.

-Activation of an oncogene, or deactivation of a tumor suppressor

Tumor Formation

Changes in DNA sequence, and/or changes in methylation


-mutated form of genes (proto-oncogenes) that stimulate cell division

Tumor Suppressor Genes

Genes that control cell division, DNA repair genes, or apoptosis genes

6 Abilities Cancer cells need to require to become metastatic

1) Self-sufficiency in growth signals
2) Insensitivity to anti-growth signals (no contact inhibition)
3) Evading apoptosis
4) Limitless replicative potential
5) Sustained angiogenesis
6) Tissue invasion and metastasis

Genetic Instability

Look at images

Proto-oncogenes and cell cycle

Act as accelerator; drive cell cycle faster: promote growth

Tumor suppressor and cell cycle

Act as brakes: elments that stop, regulate, or control the cell cycle

Oncogenes and cell cycle

Mutated version or normal gene; WORKS TOO WELL; doesn't respond to normal cell signals to stop

List of Oncogenes

Erb B2 (her2/neu): growth factor receptor

Ras: signal transduction gene

Myc: nuclear protein

Deletion/Point Mutation

results in hyperactive protein

Regulatory Mutation

normal protein greatly overproduced

Gene Amplification

Normal protein overproduced due to multiple copies of gene

Chromosome rearrangement

Gene is now under control of the wrong promoter;
-over-production of normal protein

Erb B2 Mutation Process


-encodes truncated epidermal growth factor receptor (tyrosine kinase). CONTITUTIVELY ACTIVE without EGF around

-found in certain breast cancers

Ras: normal function

1) Growth factors bind receptor, activate GRB2-SOS
2) GTP binds Ras, GDP falls off; RAS ACTIVE
3) Ras-GTP activates RAF
4) GAP activates (GTPase activating protein)
5) GTP to GDP, Ras inactive

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