Professional Documents
Culture Documents
Group no. 6
MED 1 -B2
Jamee Dela Rosa
Haiezel dela Cruz
Lalaine dela Cruz
Maureen dela Cruz
Erika dela Fuente
Mariel dela Cruz
OBJECTIVES
1. Describe the physical structure of a chromosome and describe what
makes up the centromere and telomeres of a chromosome
2. Briefly review the process of replication of a linear chromosome and
explain what accounts for the natural shortening of the lagging strand
3. Explain Cellular Senescence, some mechanisms that accounts for it and
how is it related to cancer
4. Describe the enzyme Telomerase and its structure.
5. Identify specific cell populations that express the enzyme h.
6.
7.
8.
9.
CHROMOSOME
PHYSICAL STRUCTURE
Parts:
CHROMATIDS
Double Stranded DNA
TELOMERE
Found at each end of
Chromatid
CENTROMERE
Part of a chromosome that links sister chromatids
Rich in adenine-thymine base pairs
Condensed regions within the chromosome that are
responsible for the accurate segregation of the replicated
chromosome during mitosis and meiosis
TELOMERE
Telos - END'
Mers -PART
Short thymine-guanine sequence
5-TTAGGG-3 Sequence
Found at each end of a chromatid,
which protects the end of the
chromosome from deterioration or
from fusion with neighbouring
chromosomes
KEY POINTS
ORIGIN is the beginning
REPLICATION FORKS are
the sites at which DNA
synthesis is occurring
New chains grow 5-3
Bidirectional
Semi-conservative
ORDER OF ACTION
Unwinding proteins
Preventing the Reannealing
Primase makes RNA primer
DNA polymerase makes DNA
RNAse H removes RNA primer
DNA polymerase fills in gaps
DNA ligase joins gaps
UNWINDING
OF PROTEINS
HELICASE
Made up of 6 proteins
arranged in a ring shape
Motor proteins
Unpackage an organisms
gene
PREVENTING THE
REANNEALING
SINGLE STRAND BINDING
PROTEINS
Tetramers
Attached to the postreplication fork single
strands of DNA,
preventing their
"reannealing
PRIMASE MAKES
RNA
PRIMER
PRIMASE
A type of RNA
Polymerase
Creates a RNA Primer
Key importance in
DNA Replication
DNA POLYMERASE
Creates DNA Molecules
by assembling
nucleotides
RNAse H
REMOVES RNA
PRIMER
RNAse H
Non- Specific
Endonuclease that
catalyzes the cleavage
of RNA
Removing the RNA
primer
DNA POLYMERASE
FILLS IN THE GAPS
DNA LIGASE
A ligase that facilitates
the joining of DNA strand
together by catalyzing the
formation of a
phosphodiester bond.
CELLULAR SENESCENCE
Latin: Senescere Grow Old
It is the phase or stage in which normal cells
cease to divide
Associated with a loss of telomerase activity
As human telomeres grow shorter, eventually
cells reach the limit of their replicative
capacity and progress into senescence
CELLULAR SENESCENCE
Today it is known that somatic cells derived from
human newborns will usually divide 80 to 90
times in culture
Whereas those from a 70-year-old are likely to
divide only 20 to 30 times
When human cells that are normally capable of
dividing stop reproducingor, in Hay- flick's
words, become "senescent"they look different
and function less efficiently than they did in
youth, and after a while they die.
CELLULAR SENESCENCE:
ACCUMULATION OF DAMAGE
Major cause of aging which is due to highly
reactive substances containing oxygen (oxygen
free radicals)
Oxygen free radicals damages the DNA
Damaged DNA accumulate mutations with
fewer proliferation
CELLULAR SENESCENCE:
MITOCHONDRIAL DNA DAMAGE
The mitochondria have their own genetic material
(mtDNA), which is distinct from the nuclear DNA in
the cell.
Mitochondria produce ATP (energy) and free
radical (byproducts of respiration)
Aerobic condition 4% of oxygen are metabolize by
mitochondria.
In normal condition, the oxygen is reduced to
produce water.
CELLULAR SENESCENCE:
MITOCHONDRIAL DNA DAMAGE
However, the oxygen is instead prematurely
and incompletely reduced to give the
superoxide ion.
The superoxide ion hydrogen peroxide
hydroxyl radical Reactive oxygen species
(ROS)
ROS leads to damage the cell membrane,
structural protein and mitochondrial and
nuclear DNA.
MITOCHONDRIA
ROS
CELLULAR
SENESCENCE
OXIDATIVE STRESS
AGEs
GLYCATION
WHAT IS TELOMERASE?
TELOMERASE
Background
Telomerase is an enzyme, discovered by
Elizabeth Helen Blackburn (professor of
biochemistry and biophysics at the University of
California, San Francisco School of Medicine)
and Carol Greider (professor of molecular biology
and genetics at the Johns Hopkins University
School of Medicine ) in 1985.
TELOMERASE
A ribonucleoprotein reverse transcriptase
(enzyme) that synthezises telomeric DNA.
Tetrahymena in which the enzyme was first
discovered.
Tetrahymena 5 TTGGGG 3
In humans 5 TTAGGG 3
TELOMERASE
is an enzyme that adds telomeric sequences to the
ends of each chromosome. Unlike most enzymes,
which consist entirely of protein, telomerase is a
combination of a protein and an RNA.
The enzyme is a protein and RNA complex called
telomere terminal transferase, or telomerase.
Telomerase is present in most fetal tissues, normal
adult male germ cells, stem cells, in proliferative
cells of renewal tissues, and in most tumor cells.
TELOMERASE STRUCTURE
TELOMERASE STRUCTURE
Human telomerase is composed of at least
two sub-units:
human Telomerase Reverse Transcriptase
(hTERT) - protein component
human Telomerase RNA (hTR or hTERC)
- RNA Component
MECHANISM OF TELOMERIC
LENGTHENING
hRNA
CAAUCCCAAUC
TELOMERE
hTERT
GGTTAGGGTTAGGG
CCAAUCC
TELOMERASE
STEP 1: BINDING
CAAUCCCAAUC
GGTTAGGGTTAGGG
CCAAUCC
STEP 2: ELONGATION
GGTTAGGGTTAGGGTTAGGG TTAG
CCAAUCC
CAAUCCCAAUC
STEP 3: TRANSLOCATION
GGTTAGGGTTAGGGTTAGGG TTAG
CCAAUCC
CAAUCCCAAUC
STEP 4: ELONGATION
CAAUCCCAAUC
T-loop
HETERO-DUPLEX OR T-LOOP
Importance of T-loop
stabilizes the telomere
prevents the telomere ends from being recognized
as break points by the DNA repair machinery thus
it gives protection from exonucleases.
preventing the telomere from eliciting a DNA
damage response manifested as cell-cycle arrest
or apoptosis
Importance of T-loop
prevention of chromosome end fusions or non
homologous end joining (NHEJ)
prevention of homologous recombination
between telomeric regions
regulation of telomere length homeostasis.
Shelterin Complex
The T-loop is held together by six known
proteins:
TRF1, TRF2, POT1, TIN2, RAP 1 and TPP1,
Shelterin Complex
1. TRF 1 (Telomeric Repeat
binding Factor 1)
Shelterin Complex
2. TRF2 (Telomeric Repeat
binding Factor 2)
It appears to promote
formation of D-loop
prevents
ataxia
telangiectasia
mutated
(ATM) activation, which is
a DNA damage response
(DDR) to DNA double strand
breaks.
But when DNA repair of
telomeres is required, TRF2
recruits
DNA
repair
proteins.
Shelterin Complex
3. TIN 2 (TRF1 Interacting
Nuclear factor 2)
Shelterin Complex
4. POT 1 (Protector Of
Telomeres 1)
Shelterin Complex
5. RAP1 (Repressor/Activator
Protein 1)
Shelterin Complex
6. TPP1 (TINT1, PTOP,
PIP1 POT1-TIN2
organizing protein)
AGING
What is aging?
Aging is a degenerative process that is
associated with progressive accumulation of
deleterious changes with time, reduction of
physiological function and increase in the
chance of disease and death.
but
an
Telomere shortening
When people are divided
into two groups based on
telomere length, the half
with longer telomeres lives
an average of five years
longer than those with
shorter telomeres.
Chronological Age
After age 60, the risk of death doubles every 8 years. So a
68-year-old has twice the chance of dying within a year
compared with a 60-year-old.
Oxidative Stress
Oxidative stress is the damage to DNA, proteins, and
lipids (fats) caused by oxidants, which are highly reactive
substances containing oxygen
Glycation
Glycation happens when glucose, the main sugar we use
as energy, binds to some of our DNA, proteins, and lipids,
leaving them unable to do their jobs.
DISADVANTAGES
Blackburn
cells sometimes
compensate for the loss
of telomerase, repair
shorter ends for
Recombination
THANK YOU!