mutation, dna repair, apoptosis [compatibility mode]

8/17/2019 Mutation, Dna Repair, Apoptosis [Compatibility Mode]

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MUTATIONS AND DNA REPAIR


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DNA - Gene

The gene store genetic information encoded in the sequence

of nucleotide pairs in DNA

Inheritance is based on genes that are transmitted from parentsto offspring during reproduction with considerable accuracy


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CARCINOGENESIS

Is a multistep process at both phenotypic andgenetic levels, resulting from accumulation of

multiple mutations.Stages :

Initiation

Promotion

Progression


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Proto-oncogenes

Normal cellular genes whose products promote

cell proliferation.

That can become an oncogene.


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Oncogenes

Mutant versions of proto-oncogenes that help

turn normal cell into tumor cell.


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Oncogene can promote uncontrolled cellproliferation by several mechanisms :

1- stimulus independent expression of growth

factors e.g. PDGF – PDGF receptor


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2- mutation in gene encoding growth factorreceptors e.g. EGF receptor.

3- mutation in gene encoding signaling

molecules.

4- overprotection or unregulated activity of

transcription factors.


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Mutasi

The alteration of DNA sequence

Caused trough :

- the action of damaging chemicals or

radiation or

- the error inherent in DNA replication and repair

reaction


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Types of Mutations


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Chromosomal abnormalities


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Mutation process and expression product in wild

type and mutant allel


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Recessive mutant alleles often result in blocks inmetabolic pathway

For example: 5 disorders are caused by autosomalrecessive mutation with defect in phenylalanine-tyrosin metabolisme:

-Phenylketonuria

-Tyrosinosis

-Tyrosinemia

-Alkaptonuria

-Albinism


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How about breast cancer?


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- Deaminating agent that deaminate the

amino groups in basesExample: Nitrous acid (HNO2)

- Hydroxylating agent, that hydroxylase amino

groups in the bases caused transitionmutation.Example: Hydroxylamine

- Acridin dyes, that intercalate DNA molecule,so doing, they increase the rigidity and alterthe conformation of the double helixExample: Proflavin

Acridine orange


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Some potent chemical mutagens


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2. Physical agents

- Ionizing radiation

High-energy rays collide with atom and cause therelease of electrone, creating free radical or ion. It

also induces gross changes in chromosome

structure

Examples: X-rays, gamma rays and cosmic rays

- Nonionizing radiation

Lower-energy that penetrate only the surfacelayer of cells and don’t cause ionizations.

Example: UV light cause pyrimidine hydrate

pyrimidine dimer


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3. Transposable Genetic

Elements (transposons)

DNA element that canmove from site in thegenome to another site.The insersion of atransposons will oftenrender the gene

nonfunctional.


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Three major factors for the occurring of mutation:

1. The accuracy of the DNA replication machinery

2. The efficiency of the mechanisms that have evolved

for the repair of damaged DNA.

3. The degree of the exposure to mutagenic agentspresent in the environment.


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Targets of Chemical Carcinogens

Protooncogenes: when protooncogenes are

activated by a mutational event, signals for

cell growth are increased (e.g., Ras). Tumor suppressor genes: tumor suppressor

genes regulate cell growth negatively;

relevant mutations result in a loss of function

(e.g., p53).


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Sources of damage

Can be divide into:1) endogenous damage

2) exogenous damage caused by externalagents:

radiation from the sun

other radiation including x-rays and gamma

rays certain plant toxins

viruses


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DNA repair

Identification of the mismatch strand:

when the mismatch occurs the Mut protein must

be able to know the correct strand.it is based on the degree of methylation


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Repair of damaged strand

when the mismatch identified :

Endonuclease nick the strand Exonuclease remove the mismatch


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Diseases caused by defect in

DNA repairXeroderma Pigmentosum :

Xeroderma pigmentosum (XP) results from

defects in one of seven genes (XPA-XPG)important in repairing DNA damage caused

by ultraviolet (UV) light.


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Hereditary nonpolyposis colorectal cancer

(HNPCC):

is an autosomal dominant genetic conditionwhich has a high risk of colon cancer

HNPCC defects in DNA mismatch repair lead

to microsatellite instability, also known as

MSI-H

• (microsatellite is repeated sequences of DNA)


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Evasion of Apoptosis

The accumulation of neoplastic cells requires notonly the activation of oncogenes or inactivation oftumor suppressor, but also the inhibition oravoidance of apoptosis.

Cell division is a highly regulated & orchestratedprocess, however mistakes are a regularoccurrence, these abnormal mitotic products aredirected to apoptosis either self-induced or through

interaction with classes of immune cells.


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REFERENCES :

PRESENTATION OF :

MOHAMMED AL SHAQHA

MORABET AL HEMAID

FAISAL ALOUFI

MOATH AL BARROK

MOSSAB ALRRETHEA

ABDULLAH AL OWATTED

YAZIED AL HATHAL

FACHIROH, J. & PURNOMOSARI,D. 2013.

KURSUS BIOLOGI MOLEKULER, KURSUS

BIOLOGI TUMOR. UGM.

mutation, dna repair, apoptosis [compatibility mode]

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