GENETIKA MOLEKULER

PADA NEOPLASMA
Genom DNA, Siklus Sel, Apoptosis,Telomer

dr. Ronald
dr. Ghina Aghniya
dr. Sheila Sumargo
dr. Mochamad Akbar Azizi
dr. Deddy Oskar
dr. Randhi Rinaldi
dr. Rafika Aninda Fauzia
drg. Erza Kurniawan
drg. Niken Laksmitarani
 DNA
DNA or deoxyribonucleic acid is the molecule that carries
all of the inherited information in the cell.
Composed of two chains that coil around each other to
form a double helix.

Junqueira's basic histology. McGraw-Hill Medical, 2014.

 STRUCTURE OF DNA

Each nucleotide is composed of 3

parts:
• One of four nitrogenous base,
Adenine (A), Cytosine (C),
DNA  polynucleotides Guanine (G), and Thymine (T)
• Sugar (called deoxyribose),
• Phosphate group (which is a
phosphorus atom bonded to 4
oxygen atoms).

Wheater's functional histology: a text and colour atlas. Elsevier Health Sciences; 2013.
Wheater's functional histology: a text and colour atlas. Elsevier Health Sciences; 2013.
 DNA Replication
• Involves an enzyme: DNA polymerase.
• Strands are separated. Each strand of the original DNA
molecule then serves as a template for the production of its
counterpart, a process referred to as semiconservative
replication.
 GENES
Mendel first defined genes as
information containing
elements that are distributed
from parents to offspring

A gene is the basic physical

and functional unit of heredity.

DNA of each human cell is

approximately 2 m long, with
3.2 billion base pairs (bp)
Junqueira's basic histology. McGraw-Hill Medical,; 2014.
Genome
◦ The genome is all the DNA in a cell.
◦ All the DNA on all the chromosomes
◦ Specifically, it is all the DNA in an organelle.
◦ Eukaryotes can have 2-3 genomes
◦ Nuclear genome
◦ Mitochondrial genome
◦ Plastid genome
◦ If not specified, “genome” usually refers to the nuclear
genome.
◦ In human contains approximately 30.000 genes
arranged in 23 pair of chromosomes
◦ 22 homologous pairs, the autosomes, and 2 sex
chromosomes
Junqueira's basic histology. McGraw-Hill Medical,; 2014.
 Chromosomes
• Organized structure of DNA and protein that is found in
cells
• Eukaryotes have several linier chromosomes
• Structures carrying genes
• Consist of DNA
• Located in nucleus

Wheater's functional histology: a text and colour atlas. Elsevier Health Sciences; 2013.
 Telomere
Repetitive DNA sequences at the ends of all human
chromosomes

They contain thousands of repeats of the six-nucleotide

sequence, TTAGGG
In humans there are 46 chromosomes and thus 92 telomeres
(one at each end)
They contain thousands of repeats of the six-nucleotide
sequence, TTAGGG
In humans there are 46 chromosomes and thus 92 telomeres
(one at each end)

Robbins and Cotran Pathologic Basis of Disease-Saunders (2015)

• Cellular Senescence. All normal cells have a limited capacity for
replication, and after a fixed number of divisions cells become
arrested in a terminally nondividing state.

• When somatic cells replicate, a small section of the telomere is

not duplicated, and telomeres become progressively shortened.

• As the telomeres become shorter, the ends of chromosomes

cannot be protected and are seen as broken DNA, which signals
cell cycle arrest.
• The lengths of the telomeres are normally maintained by
nucleotide addition mediated by an enzyme called
telomerase.

• Telomerase is a specialized RNA-protein complex that

uses its own RNA as a template for adding nucleotides
to the ends of chromosomes.

• Telomerase activity is expressed in germ cells and is

present at low levels in stem cells, but it is usually
absent in most somatic tissues

Robbins and Cotran Pathologic Basis of Disease-Saunders (2015)

What do telomeres do?
They protect the chromosomes.

Regulate telomerase activity at chromosome ends

They separate one chromosome from another in the DNA sequence

Without telomeres, the ends of the chromosomes would be

"repaired", leading to chromosome fusion and massive genomic
instability

Essential for chromosome stability

Telomeres are also thought to be the "clock" that regulates how

many times an individual cell can divide. Telomeric sequences
shorten each time the DNA replicates.
Telomerase and Cancer
◦ There is experimental evidence from hundreds of
independent laboratories that telomerase activity is
present in almost all human tumors but not in tissues
adjacent to the tumors.
◦ Thus, clinical telomerase research is currently
focused on the development of methods for the
accurate diagnosis of cancer and on novel anti-
telomerase cancer therapeutics
Cell Cycle

• The regular sequence of events that produce new

cells is termed the cell cycle.
• Organized sequence of complex biologic processes
that is traditionally divided into four distinct phases
 Phase of Cell Cycle
◦ Resting (G0 phase)
◦ Interphase
◦ G1 phase (growth and
preparation of the
chromosomes for
replication)
◦ S phase (DNA
replication)/ synthesis of
DNA (and centrosomes)
◦ G2 phase
◦ Mitosis (M phase)
Wheater's functional histology: a text and colour atlas. Elsevier Health Sciences; 2013.
The Cell Cycle Control System

◦ The sequential events of the cell cycle

◦ Are directed by a distinct cell cycle control
system, which is similar to a clock

Two types of regulatory proteins are involved in

cell cycle control
Cyclins
Cyclin-dependent kinases (cdks)
APOPTOSIS APOPTOSIS
• Programmed cell death = cell death induced by
• Orderly cellular self intracellular program
destruction
• Process: as crucial for “SUICIDE PROGRAM”
survival of multi-cellular
• organisms as cell division Cell
PHYSIOLOGIC: destined to die
 endometrial break down->
menstrual cycle
 during embryogenesis
Neutrophyl -> acute inflamation
Activation of
Lymphocite  immune response
enzymes
PATHOLOGIC :
 injurious stimuli : radiation,
anti
cancer drugs
Degradation of :
 viral disease : viral hepatitis  NUCLEAR DNA
Pathologic atrophy after duct  Nuclear protein
obstruction -> parotid gland  Cytoplasmic protein
 Tumors
Robbins and Cotran Pathologic Basis of Disease-Saunders (2015)
 MECHANISM OF APOPTOSIS

Robbins and Cotran Pathologic Basis of Disease-Saunders (2015)

APOPTOSIS: Role in Disease
TOO MUCH: Tissue atrophy
Neurodegeneration
Thin skin
etc

TOO LITTLE: Hyperplasia

Cancer
Athersclerosis
etc
 APOPTOSIS: Role in Disease
Cancer
Apoptosis eliminates damaged cells
(damage mutations cancer)

Tumor suppressor p53 controls senescence

and apoptosis responses to damage

Most cancer cells are defective in apoptotic response

(damaged, mutant cells survive)

High levels of anti-apoptotic proteins

or
Low levels of pro-apoptotic proteins
===> CANCER
APOPTOSIS: Role in Disease
Aging
Aging both too much and too little apoptosis
(evidence for both)

Too much (accumulated oxidative damage?)

tissue degeneration

Too little (defective sensors, signals?)

dysfunctional cells accumulate
hyperplasia (precancerous lesions)