bio chapter 14

carcinogens

- 80% of cancers are related to exposure to this -agents that increase likelihood of getting cancer -UV light and certain chemicals in cigarette smoke are mutagens that promote genetic changes in somatic cells -DNA alterations can lead to effect on gene expression that ultimately affect cell division an lead to cancer

frameshift mutation

- addition or deletion of nucleotides (excluding multiples of three) -completely different amino acid sequence downstream from mutation

NER was discovered in humans from genetic diseases that affect DNA repair

-Xeroderma pigmentosum (XP) -Cockayne's syndrome (CS) -PIBIDS

p53

-about 50% of all human cancers are associated with defects in this gene ' -G1 checkpoint ptotein -DNA damage induces expression to prevent cell from progressing from G1 to S phase -cell will process when DNA is repaired

tumor

-an overgrowth of cells with no useful purpose -tumor may begin an benign or pre-camcerous may become malignant

oncogenes

-bind to cell surface and initiate cascade, activating specific genes, leading to cell division -mutations in genes for cell growth signaling proteins can change them into oncogenes producing abnormally high levels of activity -an oncogene promotes cancer by keeping the cell division signaling pathway in a permanent "on" position

a few viruses

-cause cancer in plants, animals, and humans -some cause cancer by modifying host DNA

induced mutations

-caused by environmental agents -higher rate than spontaneous mutations -mutagens - chemical or physical agents that alter DNA

mice that are missing the p53 gene are born healthy

-cell division leading to normal growth is regulated properly -checkpoint proteins such as p53 are not necessarily for normal cell growth and division

nonsense mutation

-change from a normal codon to a stop codon -produces a truncated polypeptide

cancer

-characterized by uncontrolled cell division -most cancers (90%) do not involve heritable genetic changes

silent mutation

-does not alter the amino acid sequence -due to degeneracy of genetic code

Rb (retinoblastoma) (negative regulators)

-first tumor-supressor gene to be identified in humans by studying patients with the disease retinoblastoma -some people have an inherited from that occurs early -others form is caused by environmental agents occur later in life

spontaneous mutations

-from abnormalities in biological processes -rates vary in species to species and gene to gene

gene amplification

-increase in copy number results in too much protein -many human cancers are associate with amplification of particular proto-oncogenes

Ras

-intracellular signaling protein that hydrolyses GTP -when GTP is bound, Ras promotes cell division -oncogenic mutations may decrease ability of Ras to hydrolyze GTP or exchange GDP/GTP faster -both keep signaling pathway constantly on

malignant stage

-lost normal growth regulation -invasive- can invade healthy tissue -metastatic- can migrate to other parts of the body

nucleotide excision repair (NER)

-most common DNA repair system -region encompassing several nucleotides in the damaged strand is removed from the DNA -intact undamaged strand is used as a template for resynthesis of a normal complementary strand -found in all eukaryotes and prokaryotes

proto-oncogene

-normal gene that if mutated can become an oncogene -four common genetic changes 1. missense muations 2. gene amplifications 3. chromosomal translocations 4. retroviral insertions

tumor-supressor genes

-normal role to prevent cancerous growth -functions: 1. maintain genome integrity by monitoring and of repairing DNA damage 2. inhibitors of cell division

"two-hit" model of retinoblastoma

-people have 2 copies of the Rb gene one from each parent -individuals with the inherited form of the disease have one mutant gene already from one parent -people with the non inherited form of the disease must have two mutations in the same retinal cell to cause the disease

checkpoint proteins

-proteins called cyclins and cyclin-dependent protein kinases (sdks) are responsible for advancing cell through 4 stages of cell cycle -formation of activated cyclin/cdks complexes can be stopped by checkpoint proteins

missense mutation

-single nucleotide change results in a codon that codes for a different amino acid -may not alter function if substituted amino acid is similar in chemistry to original -example: sickle-cell disease -chemical mutagens have been shown to cause missense mutations leading to cancer

chromosomal translocations

-two chromosomes break and switch ends -very specific translocations associated with certain types of tumors -can create chimeric genes

Ames Test

-uses Salmonella typhimurium that cannot synthesize histidine due to a point mutation -bacteria cannot grow unless histidine is added to the medium -or the second mutation occurs that fires the original, allowing synthesis of histidine -test monitors rate at which second mutations occurs -allows us to test and quantify mutagenicity

Lung Cancer

-usually detected late -most lung cancers are carcinomas -epithelial cell cancers -mutations happen in basal cell developing more abnormal morphologies - dysplasia -early stages the abnormal basal cells are precancerous- when cancerous called basal cell carcinoma - metastasis of these cells to other parts of the body will typically kill the patient within a year of being diagnosed

retorviral insertions

-viral DNA inserts into a chromosome, putting a viral promoter next to photo-oncogene -if photo-oncogene becomes overexposed it will promote cancer -some viruses cause cancer because they carry an oncogene in the viral genome

binding of functional Rb protein inhibits

E2F and prevents cell division

if both copies of Rb are defective

E2F protein is always active resulting in uncontrolled cell division

methyl-directed mismatch repair

a base pair mismatch is detected, and a strand of surrounding DNA is removed and replaced

photosensitivity

a common characteristic in all three syndromes because of an inability to repair UV-induced lesions

direct repair

a direct repair enzyme recognizes an incorrect structure in the DNA and directly converts it back

cancers originate from

a single cell

malignancy can continue to

accumulate genetic changes that make it even more difficult to treat

Rb protein inhibits the transcription factor E2F, which

activates genes for G1 to S phase cell cycle progression

somatic cells

are all other body cells -can occur early or late in development -gives a genetic mosaic with patches of mutant tissue

majority of cancers

are caused by mutagens

maintain genome integrity by monitoring and/or repairing DNA damage (tumor-suppressor genes)

checkpoint proteins check the integrity of the genome and prevent a cell from progressing past a certain point in the cell cycle

mutagens

chemical or physical agents that alter DNA -induced mutation

cytogenetics

field of genetics involving microscopic examination of chromosomes and cell division

caspases

function as proteases that disgust selected cellular proteins causing the cell to break down

germ-line cells

give rise to gametes -mutation can occur in sperm or egg cell, or in gamete progenitor cells

ionizing radiation (radiation damage)

has high energy and penetrates deeply to create free radicals -X rays and gamma rays -cause deletions or breaks in one or both DNA strands

mutation within a tumor-suppressor gene

inactivate its function

chromosome loss

may contribute if the missing chromosome carries one or more tumor-suppressor genes

cancer usually requires

multiple genetic changes to the same cell

abnormal methylation of CpG islands

near the promoter regions of the tumor-suppressor gene

inhibitors of cell division (tumor-suppressor genes)

necessary to properly halt cell division otherwise division becomes abnormally accelerated

begin with benign genetic alteration that

over time and with additional mutations lead to malignancy

nucleotide excision repair

portion of DNA strand containing an abnormal nucleotide is removed and replaced

karyotype

reveals number, six, and form of chromosomes in actively dividing cells

negative regulations of cell division

secondary category of tumor-suppressing gene

disruption of replication

some insert between the bases and distort the helix -benzopurene, found in cigarettes and charbroiled food

disruption of base-pairing

some modify nucleotide structure -nitrous acid dominates bases, changing C to U, so that it pairs w/ the wrong nucleotide -mustard gas or EMA alkylate bases adding methyl or ethyl groups base analogues substitute into DNA

when checkpoint genes are broken down by mutation

the division of normal healthy cells may not be affected

mice are very sensitive to mutagens and easily develop cancer

the loss of checkpoint protein function makes it more likely that genetic changes will occur that could cause cancerous growth

if DNA damage is too severe

the p53 protein will activate other genes that promote programmed cell death or apoptosis

a mutation may alter

the sequence within a promoter and affect the rate of transcription -may enhance or inhibit transcription

loss of tumor-suppressor gene function

three common ways : 1. mutation within a tumor-suppressor gene 2. chromosome loss 3. abnormal methylation of CpG Islands