DNA Overview

Genetic Basis of Cancer PPT 1

What is cancer?

A genetic disease, is not one disease

Clone

cells that share common genetic ancestor

Cancer is a

clonal disease- originates from one ancestral cell and gives rise to limitless descendants

DNA Nucleotides

Pyrimidines and Purines

Pyrimidines

Cytosine, and Thymine

Purines

Adenine and Guanine

Molecular Structure of DNA

Phosphate group, nitrogenous base, and sugar (deoxyribose)

DNA Structure

5’ to 3’ directionality of the DNA strand.

The 5’ to 3’ indicates

which carbon the phosphate is added to form the phosphodiester bond

Mutations

can affect several areas of the central dogma process

Mutation in Promoter

may not transcribe RNA

Mutation in Gene/Structure

truncated protein loses “off switch”

Central Dogma

DNA → RNA → Proteins

Mutations can result

in several DNA variations such as mutation, amplification and chromosomal translocation

Mutation ex

changes protein structure so that it is always on

Amplification ex

increasing the copy number of the gene so there are more of the protein, and when stimulated create overwhelming response to grow

Chromosomal translocation ex

creates new “fusion protein”

What are Mutations/Variations?

Changes in the DNA

Germline

in all cells (genetic/hereditary diseases)

Somatic

in only certain cells (cancer)

Point Mutations

one nucleotide differences

Chromosomal Mutatiosn

large areas of the chromosome or gene are altered

Types of Point Mutations

silent, nonsense, missense, insertion, and deletion

Silent

does not change amino acid to be transcribed, aka nucleotide changes but amino acid stays the smae

Nonsense

results in stop codon; premature stop

Missense

changes amino acid in trancsript

Types of missense

Conservative and non-conservative

Mutations that cause missense mutations

Transitions and transversions

Transitions

substitute one purine for another (A for G)

Transversions

substitute one purine for pyrimidine (A for T)

Conservative

similar charge or strucutre amino acid substitution

Non-conservative

different charge or structure change in amino acid

Insertion

one nucleotide is added, which changes the transcript code

Deletion

one nucleotide is deleted, which changes the transcript code

Chromosome Mutations

changes in large parts of the gene or chromosome

Duplication (amplification)

parts of the chromosome or whole genes are duplicated

Inversion

parts of the chromosome are inverted and reversed

Deletion

parts of the chromosome or gene are deleted

Insertion

parts of on chromosome are added to another

Translocation

parts of two chromosomes are switched between each chromosome

Chromosome mutations/alterations

cannot be easily fixed or repaired by the cell

Why do mutations occur?

Endogenous errors, environmental (exogenous), hereditary

Endogenous errors

Accidental errors during replication. Can also be from cellular stress

Environmental (exogenous)

Factors or substances in the environment that can damage DNA

Hereditary

Inherited mutations in one copy of gene (usually tumor suppressor genes)

DNA Polymerase

enzyme responsible for replicating DNA

In DNA Replication

nucleotides are added to the 3’ end; ~3 bil nucleotides per cell, adds 700-1000 nucleotides per second

The error rate in DNA replication

1 in 100,000 to 1 in 1,000,000; varies with enzyme and condition

Proofreading activity in DNA replication

spell check during synthesis to notice and fix any errors in nucleotide pairing and additions

Inherited mutations

variations in genome are inherited from egg/sperm; typically in one copy of chromosome (tumor suppressor) ex. BRCA 1/2, TP53, PALB 2; cannot change but can screen for with genetic counseling.