the presentation gives a brief idea about how the epidemis(skin) fights against various external environmental factors that may cause serious infections or disorder, also the genetics and molecular level mechanism followed to protect the body

1. CAUSE, EFFECTS & DRAWBACKS OF HUMAN DERMAL
DEFENCE SYSTEM AT GENETIC & EPIGENETIC LEVEL
DERMAL DEFENCE
MECHANISM

2. • INTRODUCTION
• DERMATOLOGY
• BRANCHES
 FACTORS EFFECTING DERMIS
• INTRINSIC
• EXTRINSIC
• MECHANIC
DEFENCE AT GENETIC LEVEL
• DNA REPAIR
• DIRECT REVERSAL MECHNISM
• INDIRECT REVERSAL MECHNISM
Title and Content Layout with List

3. • the branch of medicine concerned with the diagnosis and
treatment of skin disorders.
• Branch of Dermatology:-
1) pediatric dermatology
2) Mohs dermatology
3) Acute adult dermatology
Dermatology

6. • Uv rays(300-400
nm)wavelength- can be
direct reversed by enzyme
photolyase
In human damage repaired by
BER, NER, mismatch repair
system
• X rays & gamma rays(ionizing
radiation)
• Industial chemicals(venyl
chloride, hydrogen peroxide)
• Thermal disruption(40-80c)
Extrinsic Factors

7. • Methylation of guanine bases-direct reversed by protein
MGMT(methyl guanine methyl transferase)
• Oxidation of bases(in mitochondria)- forming 8-oxoG and generation
of DNA strand interruption
• Hydrolysis of bases- deamination, depurination, depyrimidination
• Monoadduct and diadduct damage- change in nitrogenous bases
• Stress, alcohol, sleep deprevation, vitamin deficiency, improper
nutrition, dehydration, loss of collagen and elastin, slow cell turnover
rate, loss of fats, shrinking bones, decreased production of melanin.
Intrinsic factors

8. • Kinetic (movement) factors that affect the skin such as facial
expression, sleepy positions, gravity, act of smoking etc.
• Excessive muscular acitivity and gaining of bodily muscular
volume stretches the surface area of the skin. On aging revealed
as wrinkles.
Mechanic factors

9. • DNA related errors are of
two types:-
a) DNA Damage
b) Mutation
• Damage are physical
abnormalities in DNA such
as single-double strand
breaks, 8-
hydroxydeoxyguanine
residue, polycyclic
aromatic hydrocarbon
adducts
Defence at genetic level

10. • Cant be recognised by enzymes
• Seen in rapidly dividing cells
• DNA damages in frequently dividing cells, because they give rise to
mutations, are a prominent cause of cancer. In contrast, DNA
damages in infrequently dividing cells are likely a prominent cause of
aging.
• Epimutation is defined as abnormal transcriptional repression of active
genes and/or abnormal activation of usually repressed genes caused
by errors in epigenetic gene repression. Epimutation arises in somatic
cells and the germline.
• It is the first step of tumorigenesis and can be a direct cause of
carcinogenesis. Epimutation of DNA mismatch repair (MMR) genes
(BRCA1, hMLH1 and hMSH2) causes cancer.
Mutation & Epimutation

11. • they are specific to the type of damage incurred and do
not involve breakage of the phosphodiester backbone.
• Do not require template.
• They are specific to the type of damage incurred.
• Pyrimidine dimers(covalent bond) due to irradiation,
directly reversed by photoreactivation process with
enzyme photolyase
Direct Reversal Mechanism

12. • Translesion synthesis (TLS) is a DNA damage tolerance process
that allows the DNA replication machinery to replicate past
DNA lesions such as thymine dimers or AP sites.
• It involves switching out regular DNA polymerases for
specialized translesion polymerases (i.e. DNA polymerase IV or
V, from the Y Polymerase family), often with larger active sites
that can facilitate the insertion of bases opposite damaged
nucleotides. The polymerase switching is thought to be
mediated by, among other factors, the posttranslational
modification of the replication processivity factor PCNA.
• Translesion synthesis polymerases often have low fidelity (high
propensity to insert wrong bases) on undamaged templates
relative to regular polymerases. However, many are extremely
efficient at inserting correct bases opposite specific types of
damage.
• Pol η mediates error free bypass of lesions induced by UV
irradiation

13. Defects in the NER mechanism are responsible for several
genetic disorders, including:
• Xeroderma pigmentosum: hypersensitivity to sunlight/UV,
resulting in increased skin cancer incidence and
premature aging
• Cockayne syndrome: hypersensitivity to UV and chemical
agents
• Trichothiodystrophy: sensitive skin, brittle hair and nails

14. • During the cell cycle, checkpoint mechanisms ensure that a
cell's DNA is intact before permitting DNA replication and cell
division to occur. Failures in these checkpoints can lead to an
accumulation of damage, which in turn leads to mutations.
• Defects in DNA repair underlie a number of human genetic
diseases that affect a wide variety of body systems but share a
constellation of common traits, most notably a predisposition to
cancer. These disorders include ataxia telangiectasia(AT), a
degenerative motor condition caused by failure to repair
oxidative damage in the cerebellum, and xeroderma
pigmentosum (XP), a condition characterized by sensitivity to
sunlight and linked to a defect in an important ultraviolet (UV)
damage repair pathway.

15. • Excessive UV exposure produces structural changes (photo
damage) in all layers of the skin: Collagen and elastic fibers in
the dermis become frayed (solar elastosis); elastic tissue loses
its integrity and sags or droops, clinically appearing as
wrinkles; and connective tissue weakens and predisposes to
traumatic solar purpura
• Photo (sun) damage is the most common and most pervasive
change of aging (white) skin, known as solar lentigines and
actinic keratoses.
Effects of excessive sun bathing

16. • Effect of sun screen lotions
on the skin tone.
• Right pic: shows absorption
of UV(B & C) rays intensity
by sun screen

17. Melanin production in human
Reduced melanin or zero melanin
production(Albinism) in contrasting
geographical area is an example of
epimutation.
Blue colour of eye meant less
protection from sunlight.
Exposure to high intensity cause
irritation,burning, cataract etc

18. DNA REPAIR MODELS

19. • base excision repair (BER) is the predominant mechanism that
handles the spontaneous DNA damage caused by free radicals
and other reactive species generated by metabolism. Bases
can become oxidized, alkylated, or hydrolysed through
interactions with these agents. For example, methyl (CH3)
chemical groups are frequently added to guanine to form
7methylguanine; alternatively, purine groups may be lost. All
such changes result in abnormal bases that must be removed
and replaced.
• Enzymes known as DNA glycosylases remove damaged bases
by literally cutting them out of the DNA strand through cleavage
of the covalent bonds between the bases and the sugar-
phosphate backbone.
• The resulting gap is then filled by a specialized repair
polymerase and sealed by ligase

20. • Doublestrand breaks, which are caused by ionizing
radiation, including gamma rays and Xrays.
• These breaks are highly deleterious. In addition to
interfering with transcription or replication, they can lead
to chromosomal rearrangements, in which pieces of one
chromosome become attached to another chromosome.
• Genes are disrupted in this process, leading to hybrid
proteins or inappropriate activation of genes. A number of
cancers are associated with such rearrangements.
• Doublestrand breaks are repaired through one of two
mechanisms: nonhomologous end joining (NHEJ) or
homologous recombination repair (HRR).
• In NHEJ, an enzyme called DNA ligase IV uses
overhanging pieces of DNA adjacent to the break to join
and fill in the ends. Additional errors can be introduced
during this process, which is the case if a cell has not
completely replicated its DNA in preparation for division. In
contrast, during HRR, the homologous chromosome itself is
used as a template for repair.
Indirect reversal(mismatch repair)

21. mice deficient in the dominant NHEJ
pathway and in telomere maintenance
mechanisms get lymphoma and infections
more often => short life span

22. Caloric restriction reproducibly results in extended
lifespan in a variety of organisms, likely via nutrient
sensing pathways and decreased metabolic rate.

23. • umm.edu/programs/facial_plastic/health skin(university of
Maryland)
• www.ncbi.nlm.nih.gov
• www.clevelandclinicmeded.com
• www.scholarspedia.com
Bibliography

24. THANK YOU