Molecules To Cells 1

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Prokaryotic genome

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10^5 - 10^6 bp
genes & prot. are colinear
usually 1 chrom
circular

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Eukaryotic genome

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10^7 - 10^9 bp
junk DNA and introns(<5% coding)
sex = diploid (usually)
multiple, linear chromosomes
1* genome in Nucleus 2* in organelles like mitochondria

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Satellites/ microsatellites/alpha satellites

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Repetitive portions of the genome
1-100s of nts
micros are 3 or fewer nts
alpha are MT binding sites

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Microsatellite instability

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expansion and contraction of MiSat can cause: Huntington's, Freiderich's ataxia, myotonic dystrophy, fragile X

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Huntington's disease

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caused by >/= 35 repeats of glutamine (Q)
# repeats indicates severity/onset
more = worse/earlier

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Needed for proper maintenance of chromosomes in cells

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Centromeres and telomeres
and origins of replication

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Centromere

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Repetitive DNA sequence
b/4 mitosis generates 2 chromatids
joins sister chromatids
attachment point for kinetochores

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Kinetochore

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Mediates alignment of chromosomes along midline
pulls chromatids apart and to opposite poles

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Aneuploid

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Having an incorrect # of chromosomes
Often seen in cancers

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End replication problem

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primers leave a portion of unreplicated sequence at the end of chromosomes which will continue to shorten if not compensated for

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DNA ends

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sensitive to degradation and can be recognized by cell as damage
may cause chromosomes to fuse or cell death by checkpoint pathways

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Telomeres

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solve the problems of end replication and fusion.
short, repeated sequence
Forms T-loop on end to hide chrom end and discourage degradation and "repair"

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Telomerase

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maintain telomere length
adds telomeric repeats (3') during each replication
reverse transcriptase using intrinsice RNA as a template

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Telomeres and aging

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long = great proliferative capacity = younger

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Telomeres and cancer

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once differentiated, cells d/n prod. telomerase and eventually go into senescence. mutations can cause cells to re-express telomerase and continue to divide making telomeres continually shorter. Result: "crisis" and cell death (good) or cancer (bad)

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Senescence

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non-dividing cell state induced by short telomeres. prevents crisis and cell death

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Nucleosome

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Contains:
core octamer 2x4 histone proteins (H2a, H2b, H3, H4)
DNA wrapped 2x around octamer
DNA + histones = 10nm diameter

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Histone

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unit contributing to nucleosome
globular protein with basic tails
+ tails interact with - DNA phosphate backbone

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Solenoid

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nucleosomes packed in alpha helical formation helped by H1 linker histone
approx. 6 nucleosomes/turn
form 30nm fibers

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Loops

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solenoids organized into 20-100kb loops attached to protein scaffolds. Loops then packed together more

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Euchromatin

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Loosely organized to allow access of polymerase. Contain highly "active" sites of transcription

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Heterochromatin

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Very tightly organized, low activity or even "silent" genes

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Chromatin remodeling

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Occurs at nucleosomal level
Requires: a multi protein complex and ATP
modified interaction of histones and DNA backbones

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Modifying enzymes and fctns

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acetylation and methylation: assembly of nucleosome after rep, and reg. transc.
phosphorylation: condensation b/4 division

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Proteins

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do everything

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Protein structure

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polymers of amino acids connected by peptide bonds

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Primary structure

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amino acid sequence

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Secondary structure

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arrangement of polypeptide's backbone atoms
1. alpha helix
2. beta sheet

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Tertiary structure

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arrangement of alpha helices and beta sheets

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Quaternary structure

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two or more proteins in a complex

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Alpha Helix

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residues separated by 4 positions form H bonds: carbonyl O to an NH

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Beta sheets

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every other residue?

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Tertiary structure: three types

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1. globular
2. fibrous
3. integral membrane

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Globular proteins

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compact, spherical, non repetitive
hydrophobic inside, polar outside
tightly packed & rigid
inner O and N are H-bonding with other grps in prot

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Fibrous proteins

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highly elongated: fctn as stabilizing biological structures
Ex: collagen

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Collagen

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most abundant prot in vertebrates
maj. stress-bearing component of bones, tendons, and conn tissue
triple stranded
seq = Gly X Y x usually hydroxy-proline
needs vit C and without collagen breaks down and gets scurvy

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Membrane proteins

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Peripheral: attached to surface of membranes just like globular
Integral: embedded, v diff from glob prot (outside = hydrophobe)

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Protein-protein interactions

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must be soluble in sol'n w/o binding partners
H-bonding impt to stabilization

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Multi-domain proteins

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proteins w/ independently folding domains

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Disulfide bonds

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form btw two cysteines
stabilize tert and quart structure
prevalent in extracellular proteins

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Post translational modifications

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for activation or regulation of protein

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Proteolytic processing

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cleaved after synthesis to active form.
Insulin not active until cleaved

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Phosphorylation

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(+O to Ser, Thr, Tyr)
Activate signaling proteins
Usually involves a conformational change

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Methylation

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regulates histones for packaging DNA

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Hydroxylation

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remember collagen (hydroxy-proline)

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Glycosylation

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addt'n of carbs
usually membrane proteins
stabilizes the prot's interaction with membrane

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Structural specificity of proteins

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Allows:
1. catalyze chem rxn (enzymes)
2. bind and trnsprt sm molecules
3. bind other prot. (hormones)
4. bind DNA to control expression (TFs)

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Conformational change and function

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chages with ligand binding or chem modification
active vs inactive states
HIV protease has open (active) and closed (inactive) states

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Structure determination

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X-Ray crystallography: shoot x-rays at a crystal of the protein. takes a long time, bad for mem prots
NMR: tells dist btw nuclei to get idea of structure. must deduce and can oly do sm prots

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Proteins "controlled" by

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1. Regulation of transcription
2. Transcript splicing or RNA processing
3. Selecting which mRNAs go to cytpsm
4. Selecting which are translated
5. Selectively destabilizing certain molecules
6. Post-translational modification

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RNA Polymerase make up (prokar)

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6 subunits (b, b', 2xa, w, o) together bind randomly unless sigma is present
+Sigma = holoenzyme and the complex then recognizes promoters

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Initiation (Prok)

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Complex binds promoter (btw -10& -35)
Helicase not necessary
Only copies one strand
U for T

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Polymerase affinity (Prok)

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Dictates levels of expression of different genes.
High affinity = high expression

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Cis-acting sequences

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Sequence located near a promoter of a gene to be transcribed.
Binding site for trans-acting elements

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Trans-acting proteins/elements

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Proteins that bind to cis-acting domains and regulate gene expression.
Induced by environmental signals

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Positive regulators

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transcription activators

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Negative regulators

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repressors: bind operator sequences which overlap promoter and prevent RNAp binding.

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Types of Eukaryotic RNA Polymerase

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Pol I: in nucleolus, transcribes rRNA
Pol II: in nucleus, transc. protein encoding genes, snRNAs, snoRNAs and miRNA
Pol III: transc tRNAs, 5SrRNA, snRNA

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C-terminal Domain

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Unique to RNA Pol II
Phosphorylation of Ser in the tail regulates the enzyme

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General Transcription Factors

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Necessary for all eukaryotic RNA polymerases to recognize promoters.
Each pol has own set

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TF IIs

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There's B,D,F and H
B&D find and bind promoter
F delivers Pol II
H has helicase and unwinds

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Types of Pol II promoters

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Focused and Dispersed

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Focused promoters

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May be 1 start or small cluster of starts
TFIID is the primary TF

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Who TFIID recognizes

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TATA box
INR (initiator element)
DPE (downstream promoter element)

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TBF and TAF

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TATA Binding Factor and TATA Association Factor
Constituents of TFIID that bind the TATA box and relax the nucleosome respectively

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INR DPE BREs

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INR: Initiator element. Surrounds transc start site
DPE: Downstream promoter element. Works with INR
BREs: Bind TFIIB, flank the TATA, strengthen TFIID affinity for RNAPII

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Dispersed promoters

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Most common promoters in vertebrates
TATA-less promoters
Typically found in CpG Islands

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Proximal Promoter Elements

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within 200bp of start
approx 10bp-long control elements
few for any given gene

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Enhancers

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Greater than 200bp from start
10bp-long control elements
upstream, downstr or in introns

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PPEs and Enhancers

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Both:
work no matter where located
bind DBPs which recruit RNAP or gen TFs
may use mediators

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Mediator

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Can bind an enhancer, RNAPII, and TFDII
"bridge"

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Mutations of Promoter Elements

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Mut of TATA box, INR, and PPEs all cause decreased transcription

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Mutations of recognition proteins

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Ex: mut of TBP causes Spinocerebellar ataxia 17