Professional Documents
Culture Documents
Eastern
University
Nicanor
Reyes
Medical
Foundation
Most
Common
forms
of
DNA
Variations
Pathology
A
The
Cell
as
a
Unit
of
Health
and
Disease
1. Single
nucleotide
polymorphisms
(SNPs)
J.Q.
Gacasan,
M.D.
2. Copy
number
variants
(CNVs)
SNPs
Pathology
variants
at
SINGLE
nucleotide
positions
study
of
suffering
1%
occurs
in
coding
regions
study
of
disease
w/in
exons,
introns,
intergenic
regions,
coding
regions
study
of
cellular
abnormalities
*may
serve
as
a
marker
for
multigenic
diseases
(e.g.
Diabetes,
Hypertension)
Genome
a
full
set
of
chromosomes
CNVs
all
the
inheritable
traits
of
an
organism
different
numbers
of
large
continuous
stretches
of
DNA
Human
Genome
Project
(completed
in
April,
2003)
50%
involve
gene-coding
sequences
phenotypic
diversity
DNA
Deoxyribonucleotide
Epigenetic
Factors
hereditary
material
in
humans
and
almost
other
organisms
affect
cell
type-specific
differences
in
DNA
transcription
and
most
located
in
nucleus
(nuclear
DNA)
translation
some
in
mitochondria
(mitochondrial
DNA)
made
up
of
4
bases:
Histone
Organization
Adenine,
Guanine,
Cytosine,
Thymine
Human
Genome
3.2
billion
DNA
base
pairs
1.5%
(20,00)
protein
coding
(enzymes,
structural,
signaling)
98.5%
do
not
encode
proteins
80%
regulation
of
gene
expression
Major
Classes
of
Functional
Non-protein
Coding
Sequences
1. Promoter
and
enhancer
regions
2. Binding
sites
3. Non-coding
regulatory
RNAs
a. micro
RNAs
DNA
+
histones
Nucleosome
Chroma4n
b. long
non-coding
RNAs
4. Mobile
genetic
elements
(transposons)
Two
Basic
Forms
of
Nuclear
Chromatin:
5. Special
DNA
structural
regions
1. Heterochromatin
a. Telomeres
b. Centromeres
transcriptionally
inactive
cytochemically
dense
Organization
of
Nuclear
DNA
2. Euchromatin
transcriptionally
active
cytochemically
dispersed
Histone
Methylation
Lysine
and
Arginine
Transcriptional
activation
or
repression
Histone
Acetylation
Lysine
Histone
acetyl
transferase
(HAT)
Genetic
Variations
open
up
chromatin
Polymorphisms
Histone
deacetylation
(HDAC)
located
in
non-protein
coding
regions
condensation
of
chromatin
humans
share
>99.5%
DNA
sequences
variation
encoded
in
<0.5%
of
our
DNA
(15million
bp)
Page
1
of
8
Chromatin
organizing
factors
B. Gene
suppression
bind
non-coding
regions
control
long
range
DNA
looping
Histone
Phosphorylation
B:
Conversely,
lncRNAs
can
preemptively
bind
transcription
factors
and
thus
Serine
prevent
gene
transcription.
may
open
DNA
or
condense
it
C. Promote
chromatin
modification
DNA
Methylation
Page
2
of
8
Compartmentalized
Extracellular
part
of
plasma
membrane
w/
carbohydrates
oligosaccharides
(glycolipids,
glycoprotein)
polysaccharides
(proteoglycans)
chemical
and
mechanical
barrier
cell-cell,
cell-matrix
interaction
Plasma
membrane
diffusion
small,
non-polar
molecules
(e.g.
O2,
CO2)
hydrophobic
molecules
polar
molecule,
<
75daltons
aquaporins
augment
passive
water
transport
Carriers
and
channels
for
low
MW
species
(ions
and
up
to
1000
daltons
small
molecules)
Channel
proteins
Carrier
proteins
A.
Plasma
membrane
Protection
and
nutrient
acquisition
Receptor
mediated
and
fluid
phase
uptake
Bilayers
of
amphipathic
phospholipids
1. Endocytosis
Hydrophilic
heads,
hydrophobic
tails
uptake
of
fluid
or
macromolecules
With
heterogenous
phospholipids
assymetrically
partitioned
caveolae
clathrin
2. Exocytosis
export
of
large
molecules
3. Transcytosis
between
apical
and
basolateral
compartments
Phospholipids
1.
Phosphatidylinositol
electrostatic
scaffold
for
intracellular
proteins
nd
generate
intracellular
2
signals
1.
Phosphatidylserine
electrostatic
CHON
interactions
apoptosis
eat
me
signal
2.
Glycolipids
&
Sphingomyelin
cell-cell
&
cell-matrix
interactions
B.
Cytoskeleton
inflammatory
cell
recruitment
shape,
polarity,
organize
relationship
of
intracellular
organelles
sperm-egg
interactions
Major
classes
of
cytoskeletal
proteins:
LIPID
RAFTS
1.
Actin
microfilaments
for
horizontal
interactions
2.
Intermediate
filaments
3.
Microtubules
Proteins
and
Glycoproteins
1. Ion
and
metabolite
transport
Eukaryotic
cytoskeleton:
2. Fluid-phase
and
receptor
mediated
uptake
of
Actin
macromolecules
Microtubules
3. Cell-ligand,
cell-matrix,
cell-cell
interactions
Nuclei
*function
together
as
large
complexes
Page
3
of
8
Actin
5-9
nm
G-actin
(globular
protein
actin)
non-covalently
polymerized
into
F-actin
(long
filaments)
F-actin
intertwine
to
form
double
stranded-helices
determine
shape
of
cells
surface
necessary
for
whole
cells
locomotion
Intermediate
filaments
10
nm
large,
heterogeneous
family
2. Anchoring
junctions/
desmosomes
for
tensile
strength
mechanically
attach
cells
(and
their
cytoskeletons)
to
provide
mechanical
strength
other
cells
or
to
the
ECM
resistance
to
shear
stress
spot
desmosome/macula
adherens
nuclear
morphology
and
transcription*
(small)
between
cells
major
structural
proteins
of
hair
and
skin
belt
desmosome
lamin
(A,B,C)
(broad)
between
cells
vimentin
hemidesmosome
desmin
cell-ECM
neurofilaments
Cadherins
glial
fibrillary
acidic
protein
(GFAP)
spot
desmosomes:
desmogleins,
desmocollins
cytokeratins
belt
desmosomes:
E-cadherins
Disease
associated:
Integrins
muscular
dystrophy
in
Progeria
due
to
lamin
mutation
transmembrane
connector
in
hemidesmosomes
Focal
adhesion
complex
Microtubules
large
25
nm
located
at
hemidesmosomes
dimers
of
-
and
-
tubulin
with
+
and
-
ends
generate
intracellular
signals
with
increased
shear
stress*
determines
the
positions
of
membrane
enclosed
organelles
and
3. Communicating/
gap
junctions
direct
cellulartransports
for
passage
of
chemical
or
electrical
signals
between
microtubule
organizing
center
(MTOC
or
centrosome)
where
the
cells
-
end
is
embedded
connexons
(hexamers
of
connexins)
long
highways
pores
preferred
track
for
long
distance
transport
permit
passage
of
ions,
nucleotides,
amino
acids,
plus
ends
us.
pointed
out
to
the
periphery
and
the
minus
ends
vitamins,
other
small
molecules*
towards
the
center
of
the
cell
D.
Endoplasmic
Reticulum
C.
Cell-cell
interactions
site
of
synthesis
of
transmembrane
proteins
and
lipids
for
plasma
membranes
and
cellular
organelles
protein
modifications
occurs
here:
folding,
formation
of
polypeptide
complexes,
disulfide
bonds
formation
chaperone
proteins
retain
unmodified
proteins
****failure
to
modify
leads
to
protein
degradation
in
cystic
fibrosis:
(+)
CFTR
protein
mutation,
misfolding
occurs
>>>
ER
retention
and
degradation
>>>
capacity
exceeded
>>>
ER
stress
response
>>>
apoptosis
1. Occluding/
tight
junctions
E.
Golgi
Apparatus
seal
adjacent
cells
together
stacked
cisternae
a
continuous
barrier
progressive
CHON
modifications
from
cis
(near
ER)
to
trans
(near
restricts
paracellular/
cell
to
cell
movement
of
ions
PM)
sets
boundary
between
apical
and
basolateral
cell
recycling
and
dispatching*
domains
Page
4
of
8
F.
Lysosomes
C.
Cell
death
membrane
bound
with
about
40
acid
hydrolases*
regulate
balance
of
cell
survival
and
death
intracellular
catabolism
2
major
pathways:
pinocytosis
or
endocytosis*
1.
Necrosis
autophagy
external
cell
injury
phagocytosis
(
Toxin,
ischemia,
trauma)
2.
Apoptosis
(programmed
cell
death)
G.
Proteasome
degrades
cytosolic
proteins
(denatured/
misfolded)
bound
to
ubiquitin
CELLULAR
ACTIVATION
Cell
signaling
to
differentiate
to
proliferate
to
perform
special
functions
to
continue
living
*no
signal,
cell
die
by
apoptosis
Signals:
1.
Damage
to
neighboring
cells
and
pathogens
(danger
signals)
CELLULAR
METABOLISM
AND
MITOCHONDRIAL
FUNCTION:
2.
Contact
with
neighboring
cells
(gap
junction
signals)
energy
generation
3.
Contact
with
ECM
intermediate
metabolism
4.
Secreted
molecules
(GFs,
cytokines)
cell
death
Signaling
based
on
distance
1. Paracrine
Mitochondria
2. Autocrine
have
small
genome
3. Synaptic
capable
of
replication,
transcription
and
translation
4. Endocrine
mtDNA
maternally
inherited
Receptors
A.
Energy
generation
Intracellular
receptors
transcription
factors
activated
by
lipid-soluble
ligands
Cell-surface
receptors
transmembrane
proteins
w/
extracellular
domains
that
bind
soluble
secreted
ligands
SIGNAL
TRANSDUCTION
PATHWAYS
cellular
receptors
modular
signaling
proteins,
hubs,
and
nodes
transcription
factors
(TF)
B.
Intermediate
metabolism
intermediates
are
used
to
make
lipids,
nucleic
acids,
and
proteins
Page
5
of
8
Cellular
receptors
Key
functions
of
ECM
1.
Receptors
associated
with
kinase
activity
(RTKs)*
1.
Mechanical
support
2.
Non
receptor
tyrosine
kinase
based
receptor
2.
Cell
proliferation
control
3.
G-protein
coupled
receptors
3.
Scaffolding
for
tissue
renewal
4.
Nuclear
receptors
4.
Establishment
of
tissue
microenvironment
5.
Other
receptors
Two
basic
forms
of
ECM
1. Interstitial
matrix
2. Basement
membrane
Components
of
ECM
1.
Fibrous
structural
CHONs
collagen
and
elastin
2.
Proteoglycans
and
hyaluronan
3.
Adhesive
glycoproteins
fibronectin,
laminin,
integrins
Receptor
activation
leads
to
orderly
sequence
of
biochemical
intermediates
that
Collagen
leads
to
changes
in
gene
expression
3
polypeptide
chains
ropelike
Results
in
multiple
effects
fibrillar,
non-fibrillar
enzyme
activation/inactivation
diseases
assocd:
TF
localization
(nuclear/cytoplasmic)
Osteogenesis
imperfecta
TF
activation/inactivation
Ehlers-Danlos
syndrome
actin
polymerization/depolymerization
CHON
degradation/stabilization
Elastin
activation
of
feedback
mech.
(inhibitory/stimulatory)
gives
ability
to
recoil
and
recover
shape
in
cardiac
valves
and
large
blood
vessels
Transcription
factors
associated
with
fibrillin
activation
and
nuclear
localization
of
TFs
modulates
gene
disease
assocd:
Marfan
syndrome
transcription
MYC,
JUN,
p53
Proteoglycans
resistance
to
compressive
forces
Growth
factors
and
receptors
lubrication
in
joint
cartilage
GF
role
to
stimulate
activity
of
genes
for
cell
growth
and
cell
consists
of
long
polysaccharides
division
Glycosaminoglycans
(keratan
sulfate
and
chondroitin
sulfate)
reservoir
for
growth
factors
associated
with
hyaluronan
Fibronectin
provide
scaffolding
for
ECM
deposition,
angiogenesis,
and
reepithelialization
in
healing
wounds
a
large
disulfide
linked
heterodimer
in
tissue
and
plasma
forms
Laminin
most
abundant
glycoprotein
in
BM
820
kD
cross-shaped
heterotrimer
connects
cells
to
underlying
ECM
components*
also
modulate
cell
proliferation,
differentiation,
and
motility
Integrins
transmembrane
heterodimeric
glycoproteins
with
and
subunits
allow
cells
attach
to
ECM
components
(laminin
and
fibronectin)
Interaction
with
Extracellular
matrix
on
WBC
adhesion,
transmigration
cell
interactions
with
ECM
are
critical
for
development
and
platelet
aggregation
healing,
and
maintaining
normal
tissue
architecture
Page
6
of
8
trigger
signaling
cascades
in
locomotion,
proliferation,
shape,
Good
detection
of
DNA
irregularities
differentiation
delays
cell
cycle
progression
triggers
repair
mechanisms
Cell
population
maintenace
if
cannot
be
repaired,
apoptosis
is
activated
or
senescence
(p53)
1. Proliferation
and
cell
cycle
2. Stem
cells
Defective
CDKI
checkpoint
proteins
allows
division
of
damaged
cells
potential
for
malignant
tumor
formation
Warburg
effect
example
of
an
event
that
promote
changes
in
cellular
metabolism
that
support
growth
marked
by
increased
cellular
uptake
of
glucose
and
glutamine,
increased
glycolysis,
and
decreased
oxidative
phosphorylation
Stem
cells
Cell
cycle
sequence
1.
G1
presynthetic
growth
2.
S
DNA
synthesis
3.
G2
premitotic
growth
4.
M
mitotic
growth
G0
state
where
quiescent
cells
are
Cell
cycle
activators
and
inhibitors
give
rise
to
all
the
various
differentiated
cells
cyclins
(>
15)
in
adult
organisms:
replace
damaged
cells,
maintain
tissue
cyclin
dependent
kinases
(CDKs)
populations
CDK
inhibitors
Important
characteristics
of
stem
cells
1. Self-renewal
2. Asymmetric
division
one
daughter
cell
differentiates,
other
remains
undifferentiated
and
retains
self-renewal
capacity
Stem
cell
varieties
1.
Embryonic
stem
cells
(ES
cells)
2.
Tissue
stem
cells/Adult
stem
cells
Embryonal
stem
cells
most
undifferentiated
in
the
inner
cell
mass
of
blastocyst
limitless
cell
renewal
capacity
can
give
rise
to
every
body
cell
totipotent
Cell
cycle
checkpoints
replication
of
cells
with
genetic
imperfections
is
hindered
done
by
CDK
inhibitors
1.
G1-S
monitors
DNA
integrity
2.
G2-M
ensures
accurate
genetic
replication
Page
7
of
8
Tissue
stem
cells
admixed
intimately
with
differentiated
cells
protected
within
stem
cell
niches
limited
only
produce
cells
of
a
particular
tissue
STEM
CELL
NICHES
Regenerative
medicine
theoretically:
stem
cells
can
be
used
to
repopulate
damaged
tissues
or
construct
an
entire
organ
(+)
problems:
integration,
immunogenecity
Induced
pluripotent
SC
(iPS
cells)
derived
from
patients
themselves
(-)
rejection
reaction
Cas
9
technology
with
guide
RNAs
(CRISPRs)
selectively
alter
or
correct
DNA
sequences
Trans
DB
Link:
https://www.dropbox.com/sh/xmcmo6n7ecpwxqz/AAAay5-
hcrZrkQc76PWv-G9Pa?dl=0
Yne
sytivilibagon,
Drogon.
Fight
for
me
Drogon.
Page 8 of 8