SFM Flashcards
How much of the total volume of a cell does the nucleus take up and what is its main functions?
6% of the total volume of the cell.
Role: cell regulation, proliferation, DNA transcription
RNA Virus
Reverse transcriptase
EX: HIV
DNA is…
Double stranded and antiparallel
goes from 5’ to 3’.
What type of bond is there in A-T
Double bond
What type of bond is there in G to C
triple bond
Why are mitotic chromosomes condensed 500 times when compared to interphase chromosomes?
TO prevent physical damage to the DNA as chromosomes are separated and passed on to daughter cells.
How many hydrogen bonds are formed between DNA and the histone octamer in each nucleosome?
142 Hydrogen bond
Histone proteins….
are highly conserved across species
What are the two classes of proteins that bind to DNA?
Histone proteins and Non-histone chromosomal proteins
What makes up a nucleosome core particle?
eight histone proteins
What is Chromatin made from
Protein + DNA
“beads on a string”
What is DNA wound around?
Histone octamer
Euchromatin
lightly packed form of chromatin
highly enriched in genes
usually under active transcription
92% of the human genome
What year did watson and crick describe the helical structure of DNA?
1953
What year was the genetic code determined?
1966
What happened in Feb, 2001 in regards to the human genome project?
the sequence of the human genome was announced, but only 90% was sequenced.
Replication fork
bi-directional DNA replication
Asymmetric: leading strand is synthesized continuously. Lagging strand is synthesized in segments.
Topoismerase
Relieves overwound supercoils in DNA replication.
Called DNA gyrase in bacteria
What kind of pharmaceutical drugs are used as anti-cancer agents?
Drugs that target DNA topoisomerase.
How do Topoisomerase act as inhibitors as anti-cancer agents
block the cell cycle, generate single and double stranded breaks, harms the integrity of the genome,
Leads to apoptosis and cancer cell death.
Depurination
Guanine is removed. 5000 purine lost, bases/day
Deamination
Amino group is removed from cytosine, and C gets changed to a Uracil.
This means that when it is replicated, half the daughter cells will be normal and half will have the mutation.
100 bases/day
What does methylation of CpG islands do?
stably silences genes (Cancer/DNA repair genes)
What does deamination of methyl-C produce?
turns it into a Thymine, which gets mismatched with a T
Cross-linking and intercalating
Benzo(a)pyrene –> BPDE (an epoxide)
Pro-carginogen is changed into a carcinogen
Done by metabolism (metabolism of well-done grilled meats)
Cross-linking agents
Nitrogen Mustard
Cisplatin
Mtiomycin C
Carmustine
Alkylating agents
Dimethyl Sulfate (DMS) Methyl methanesulfonate (MMS)
Intercalating agents
Thalidomide
What are the variable outcomes of DNA damage in our bodies?
It can be repaired–> normal cellular function
Not repaired/inapropro response –> deleterious consequences–> impaired cellular function, cell death, mutations or genetic instability.
Xeroderma Pigmentosum
Skin of people with this disease is very sensitive to direct sunlight, and they are prone to developing melanomas and squamous cell carcinomas.
UV component of sunlight causes cyclobutane thymine dimers to form in DNA, which can normally be repaired by NER. But individuals with this disease have defects on carious XP proteins in the NER complex and therefore exhibit the disease.
Hereditary nonpolyposis colorectal cancer
If you have a mutation on one of the alleles of the genes in the MER complex, you are more susceptible to HNCC. An acquired mutation in the remaining copy of the good gene would render the MER system nonfunctional, allowing tumor development.
Nonhomologous end joining and what disease is it associated with?
A double strand of DNA breaks, then DNA-dependent protein kinase and Ku proteins bind to the ends of the double strand break. nucleases remove several bases from both ends and then DNA ligase joins them together.
Hereditary nonpolyposis colorectal cancer
Cockayne Syndrome
autosomal recessive, congenital disorder. Mutations in ERCC6 and ERCC8–> code for genes that are involved in TCR of DNA. If DNA is not repaired, cell dysfunction and cell death may occur. RNA polymerase is permanently stalled at sites of damage in important genes. defect in transcription-coupled repair
Symptoms: neurological delay, photosensitivity, progeria (premature aging), hearing loss, eye abnormalities. Usually die within 20 years.
BRCA associated with breast cancer
BRCA 1 ( breast cancer susceptibility gene 1) and BCRA 2 are tumor suppressor genes. Mutations of these genes increases a woman’s liklihood of getting breast cancer by 5. Also at risk for developing other cancers
Homologous recombination
linked to causing breast cancer.
Types of DNA repair
Direct repair (enzymatic repair), Base exclusion repair, nucleotide excision repair (NER), Mismatch excision repair (MER), recombination repair (non homologous end joining, homologous end joining), transcription-coupled repair, translation synthesis.
Nucleotide excision repair, type of repair, enzymes associated with it, associated disorder
Repairs chemical adducts that distort DNA (ex: pyrimidine dimers, BPDE-guanine adduced, cisplatin adducts)
NER protein complex, DNA polymerase, DNA ligase
Associated with Xeroderma pigmentosum
Mismatch excision repair, type of repair, enzymes associated with it, associated disorder
repairs mismatched base in daughter strand.
MER complex, helices/endonuclease, DNA polymerase, DNA ligase
Hereditary nonpolyposis colorectal cancers
Where is the genetic defect in colon cancer? what enzyme or process is affected?
MSH2, 3, 6, MLH1, PMS2
mismatch repair
Where is the genetic defect in skin cancer, UV sensitivity, neurological abnormalities? what enzyme or process is affected?
Xeroderma pigmentosum groups A-G
Nucleotide excision-repaor
Where is the genetic defect in leukemia, lymphoma, x-ray sensitivity, genome instability? what enzyme or process is affected?
Ataxia Telangiectasia
ATM protein, a protein kinase activated by double stand breaks
Where is the genetic defect in Breast, ovarian, and prostate? what enzyme or process is affected?
BRCA2
repair by homologous recombination
Where is the genetic defect in congenital abnormalities, leukemia, genome instability? what enzyme or process is affected?
Fanconi anemia groups A-G
DNA interstrand cross-link repair
What are histone deacetylases?
HDACs- enzymes that remove acetyl groups from the lysine on core histones and nonhistone proteins. Cancer cells are very sensitive to inhibitors of such lysine deacetylases. Inhibitors are used as anticonvulsives and anticancer drugs.
Inhibitors of HDACs
valproic acid and vorinostat
what is epigenetics
a mechanism for regulating gene activity independent of DNA sequence that determines which genes are turned off or on:
in a particular cell type
in a different disease status
in response to a physiological stimulus
What factors influence epigenetic mechanisms
development in utero, environmental chemicals, drugs, aging, diet
T/F DNA methylation represses gene transcription when at a gene promoter
true
Autosomal dominant inheritance
Only 1 allele of a gene is needed for expression.
Unaffected individuals don’t show trait (aa)
Can be transmitted via male or female.
Trait is expected in every generation
recurrent risk is 50%
Autosomal recessive inheritance
2 copies of mutant allele is needed to show expression.
Females and males affected equally
X-linked recessive
Disease allele is on X in males is called homozygous
Always expressed in male carriers
Never father to son transmission
Lyionization
x inactivation
Mitochondrial DNA
double stranded and circular.
encodes rRNA, tRNA, and 13 polypeptides.
Transcription takes place in mitochondria.
Doesn’t have introns.
Inherited exclusively through the maternal line.
Why is mutation rate higher in mitochondria DNA?
They lack DNA repair mechanisms. Damage from free oxygen radicals from OXPHOS.
Mitochondrial inheritance
all offspring is affected.
there is a threshold you have to reach in order to express the gene.
Leber’s hereditary optic neuropathy
Mitochondrial disorder.
Degeneration of retinal ganglion cells.
Caused by one of three pathogenic mtDNA point mutations affecting NADH dehydrogenase–> RGC don’t have enough energy to transmit signals to the brain.
Acute loss of central vision, blind by 20’s.
Myoclonic epilepsy and ragged red fibers (MERRF)
Mitochondrial disorder.
Caused by mutation in the gene encoding for tRNA for lysine, which disrupts the synthesis of cytochrome-C oxidase.
Pt presents with myoclonus dinated muscle movements (ataxia) and seizures. Mainly affects muscles and nerves
Has a large variability, due to heteroplasmy
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
Mitochondrial disorder.
Affects brain, nervous system, and muscles. Stoke and dementia, diabetes, deafness, cognitive impairment, short stature, migraine.
Caused by single point mutation. Cant use pyruvate, so lactic acid builds up.
X-Linked dominant
No carriers. Males with disease transmit 100% to females.
Females transmit trait to males and females (50% transmission)
Euploid
cells with normal number of chromosomes
Polyploidy
Cells contain a complete set of extra chromosomes
Aneuploidy
cells contain a missing or additional individual chromosome. Can be caused by a nondisjunction during meiosis.
Genomic imprinting
We receive an active copy of each gene from each of our parents. Genomic imprinting means only one is expressed.
Imprinted alleles are silenced, and gene is expressed for non-imprinted allele.
Epigenetic process that involves methylation and histone modification of egg or sperm, while genetic sequence is unchanged.
Pattern is duplicated in all somatic cells.
Uniparental disomy
when an individual receives two copies of a chromosome or part of each chromosome from one parent and no copies from the other.
T/F for genomic imprinting, a phenotypically normal individual would only have one transcriptionally active copy of the gene
True
Where does most genomic imprinting occur?
In regions containing other clusters of imprinted genes. Through methylation of 5’ region of gene.
Epigenetic imprints in somatic cells
imprints remain throughout the lifespan of the individual in somatic cells
Epigenetic imprints in germ cells
imprints are reset at each generation. In meiosis, imprints are erased and new ones are set.
Inversion
segment of chromosomal DNA is present in its reverse orientation
Deletion
segment is lost
Duplication
segment is copied, resulting in amplification of genes contained to that region
Translocation
Different chromosomes exchange segments of their DNA. can be balanced or unbalanced.
Translocations in non-homologous chromosomes
non-homologous chromosomes exchange genetic material, it is reciprocal
Robertsonian translation
Long arm of two afrocentric chromosomes combine, the short arm is typically lost.
Karyotyping
technique that allows the determentaiton of the number, size and gross structures of chromosomes in metaphase to be examined.
Turner syndrome
Karyotype: 45, XO
female, due to absence of Y.
Symptoms: short, ovarian hypo function/premature ovarian failure, don’t undergo puberty, infertile, webbed neck, low hairline on neck, CV defects, NO cognitive defects.
Prader-willi syndrome
Deletion of a region of chromosome 15.
On the paternal chromosome.
Presentation: short, hypotonia, small hands/feet, obesity, mild to moderate intellectual ability, uncontrolled eating.
Angelman Syndrome
Deletion of chromosomes 15 on maternal chromosome.
Presentation: severe intellectual disability, seizures, ataxic gait.
Klinefelter syndrome
Karyotype: 47, XXY
Presentation is variable: cognitive-social-behavorial-learning difficulties, hypogonadism (low T), small or undefended testes, gynecomastia, infertile, tall, variability in X (XXY, XXXY) can increase symptoms.
Downs syndrome
Trisomy at chromosome 21. Increases with increased maternal age.
Most commonly from maternal meiotic nondisjunction, but can also be from unbalanced translocation.
Varying degrees of cognitive impairment.
Structural abnormalities: increased nuchal translucency, cardiac defects, duodenal atresia, ventruculomegaly, absent nasal bone, short limbs.
Edward’s syndrome
Trisomy at chromosome 18.
Often IUGR.
95% die in utero.
<10% of live births survive to one year.
Presentation: prominent occiput, malformed and low set ears, small mouth and jaw, cleft lip, rocker bottom feet, overlapped fingers.
Patau Syndrome
Trisomy at chromosome 13. Severe developmental abnormalities. 1/12,500 births. most die before birth.
Presentation: heart abnormalities, kidney malformations, CNS dysfunction, microcephaly, malformed ears, closely spaced/absent eyes, clenched hands and polydactyl, cleft lip.
Reduced penetrance
The frequency a gene manifests itself.
EX: if 100% of people who inherit a genetic defect show the clinical presentation then it is 100% penetrance.
Variable expressivity
describes the range of phenotypes that vary between individuals with a specific genotype.
EX: neurofibromatosis: patients have cafe-au-lait spots that differ in number, shape, size, and position
Marfan Syndrome
Has variable expressivity.
Affects connective tissue, have weakened or stretched aorta, may lead to aneurysm and aortic dissection.
Locus Heterogeneity
single disorder or trait, caused by mutations in genes at different chromosomal loci. Only one mutant locus is needed for the phenotype to manifest.