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SFM Exam 2 > Genomic Regulation > Flashcards

Genomic Regulation Flashcards

1
Q

What are the three types of DNA damage?

A

spontaneous, physical agents (radiation) and chemical agents (direct and indirect)

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2
Q

Describe spontaneous DNA damage

A

The most frequent type happens on a daily basis

Most frequent examples: deamination and depurination

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3
Q

What are the two types of radiation caused DNA damage?

A

Ionizing and non-ionizing

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4
Q

Describe non-ionizing radiation damage

A

UV radiation/UV induced DNA damage

Formation of pyrimidine dimers (T-T dimers)

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5
Q

Describe ionizing radiation DNA damage

A

Have high energy photons (like x or gamma ray)

Damage includes direct (bond breaking) or indirect (H2O hydrolysis and free radical formation)

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6
Q

What are the different types of ionizing radiation induced DNA damage?

A

Base damage, double and single stranded breaks, intercalation, inter-strand and intra-strand cross linkage, DNA-protein or protein-protein crosslink

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7
Q

What is the most common and most damaging type of ionizing radiation induced DNA damage?

A

double stranded breaks

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8
Q

What are the two types of chemical agents that can cause DNA damage?

A

Direct and indirect

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9
Q

What are direct chemical agents?

A

Agents that act directly to modify DNA

ex. Cross-linking agents, alkylating agents, intercalating agents

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10
Q

What do cross linking chemical agents do to DNA?

A

makes covalent bonds which prevents the strands from opening
ex. nitrogen gas, cisplatin, mitomycin and camustine

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11
Q

What do alkylating chemical agents do to DNA?

A

add a methyl group to the DNA bases

ex. dimethyl sulfate, methyl methanesulfonate

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12
Q

What do intercalating chemical agents do to DNA

A

Kills cancer cells by damaging their DNA (but can be harmful to our cells too)
ex. ethidium bromide, thalidomide, daunomycin, doxorubicin

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13
Q

What are indirect chemical agents?

A

Agents that require metabolic activation
ex. BPDE and aflatoxin which both turn into epoxides (complexes of benzene rings that form adducts between guanine bases)
Cytochrome P450 takes care of a lot of these

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14
Q

What are the 4 major types of genome alterations?

A

Chromosomal mutations, transposons, single nucleotide polymorphisms (SNP) and gene amplification

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15
Q

What are the 4 types of chromosome mutations?

A

deletions, translocation, duplication, and inversion

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16
Q

What is a deletion?

A

chromosome segment is lost

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17
Q

What is a translocation?

A

segment of chromosome is transferred to another

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18
Q

What is a duplication?

A

a segment from one chromosome is transferred to its homologous chromosome giving it a duplicate of some genes

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19
Q

What is an inversion?

A

Segment of chromosome arm is inverted

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20
Q

What is an example of a chromosome mutation?

A

Translocations can cause Down Syndrome (4% of pts with Down syndrome)

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21
Q

What are transposons?

A

Jumping genes
Mobile sequences of DNA that can change position within genome of a single cell
copy, cut and paste
Retrotransposons (reverse transcription) and DNA transposons (section gets cut and pasted in a different spot)

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22
Q

What is an example of a disease caused by transposons?

A

Hemophilia A which is a hereditary bleeding disorder caused by lack of blood clotting factor 8
W/out enough factor 8 blood cannot properly clot to control bleeding
Transposon L1: inserted into factor 8 gene and makes it ineffective

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23
Q

What are single nucleotide polymorphisms (SNP)?

A

Not mutations but can act like them
Are uncommon alterations in the DNA
A common inherited change in a single bp that occurs in at least 1-5% of the population
Occurs once every 1000-2000 its
Used to make markers in the mapping of genomes and also in drug development
May be associate with susceptibility to disease

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24
Q

What is gene amplification?

A

All the 3 previous types of genome alterations can lead to gene amplification
Other cause can be impaired replication
It can be good (more copies of the gene = less selective pressure/less mutational effects in evolution)
In diseases such as cancer and cancer therapy resistance

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25
Q

What are the two main outcomes of DNA repair?

A

DNA is repaired and normal cell function is repaired
DNA is not repaired or inappropriate response to damage occurs due to defects in DNA repair and/or damage detecting mechanisms

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26
Q

What are the two consequences of DNA not being repaired due to an inappropriate response to the damage or faulty repair mechanism?

A

Deleterious consequences

No deleterious consequences in which the cell normal cell function is regained

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27
Q

What are the deleterious consequences of faulty DNA repair?

A

Impaired cell function or cell death which lead to impaired function in the organism
Mutations or genetic instability which leads to cancer

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28
Q

What is the general scheme of action for DNA repair systems?

A

Recognize damaged DNA strand
Excision of damage
DNA polymerase makes repair
DNA ligase seals nick (religate)

29
Q

What kind of damage does direct repair fix?

A

UV damage: adjacent pyrimidines (ex. thymine dimers)

Alkylating mutagens

30
Q

How does direct repair fix UV damage?

A

Can be repaired by NER

Photolyase repairs the thymine dimers in other organisms however humans lack this enzyme

31
Q

How does direct repair fix alkylating mutagens?

A

Enzyme: methyltransferase

Moves the alkylating methyl from the DNA to itself repairing the DNA

32
Q

What type of damage is repaired with BER?

A

Single base mismatches, small non-distorting alterations, spontaneous dupurination and spontaneous deamination, uracil, 8-oxoguanine, 3-methyladenine and basic sites

33
Q

Describe the process of BER

A

Altered base detected by DNA glycosylase which then removes the base
AP endonuclease cuts phosphodiester bond
AP lyase removes deoxyribose phosphate
DNA polymerase beta replaced excised nt
DNA ligase seals nick

34
Q

What type of damaged is repaired in NER?

A

Chemical adducts, alteration in DNA shape in a local area and UV, BPDE-gaunine adducts as well as cisplatin adducts

35
Q

What is Xeroderma Pigmentosum?

A

Genetic disorder of DNA repair in which pts carry mutation in the nt repair enzymes mostly an endonuclease
sx: high sensitivity to light, pigmentary skin changes, prone to developing melanomas and squamous cell carcinomas
Autosomal recessive
Defect in NER complex XP proteins (XP-A thru XP-G)

36
Q

Describe the process of NER

A

NER complex recognizes distortions and nicks DNA on both sides of damage site
Remove stretch of DNA w/ damage
DNA pol epsilon fills the gap
DNA ligase seals the nick

37
Q

What type of damage is repaired with transcription coupled repair (TCR) (a form of NER)?

A

RNA pol stalled at a lesion in DNA

TCR proteins called ERCC-6 and ERC8: recognize stalled RNA pol and recruit repair proteins

38
Q

What is Cockanye syndrome?

A

Autosomal recessive
Mutant genes: ERCC6 and ERCC8 (TCR)
sx: neurologic delay, photosensitivity and progeria (premature aging)
Also common: hearing loss and eye abnormalities

39
Q

What type of damage is repaired with mismatch repair mechanisms (MER)?

A

During DNA replication, mismatched nt occasionally gets inserted into the newly synthesized daughter strand

40
Q

What is hereditary non-polyposis colorectal cancer?

A

Lynch syndrome
Mutations in one of the alleles of genes in MER complex
Accumulation of unrepaired DNA damage leads to genomic instability –> cancer

41
Q

What type of damage is repaired with recombination repair mechanism?

A

Double stranded breaks

Radiation and chemical damage

42
Q

What are the two types of recombination repair?

A

NHEJ and homologous repair

43
Q

What damage is repaired with NHEJ?

A

Chromosomal translocation and neoplastic chromosomal rearrangements

44
Q

Explain NHEJ

A

DNA PK and Ku proteins bind to the double stranded break
Nucleosome removes bases from both ends
Ligase joins ends together

45
Q

What is homologous recombination (HR)?

A

Needs a template
Occurs after DNA replication and before cell division
ex. Breast cancer

46
Q

Explain breast cancer and its association with HR

A 
Susceptibility genes (BRCA1 and 2): associated with hereditary breast cancer encode proteins that facilitate HR 
5x increased risk of developing breast cancer and other cancers
47
Q

What are the exceptions of the genetic code that occur in the mitochondria?

A

Codons AUA and AUU code for Met instead of Ile
AGA and AGG are stop codons instead of Arg
The standard stop codon UGA codes for Trp instead

48
Q

Mutations in the coding region (also called open reading frame ORF) lead to what?

A

To different AAs being incorporated into the protein

To different outcomes categorized into 4 types of point mutations

49
Q

What are the 4 types of point mutations seen in coding regions?

A

Silent, missense, nonsense and frameshift mutations

50
Q

What are silent mutations?

A

Codon containing the changed base may code for the same AA

ex: serine codon UCA is given a different third base U to become UCU, it still codes for serine

51
Q

What are missense mutations?

A

Codon containing changed base may code for a different amino acid
ex. If serine codon UCA is given a different first base C to become CCa it will code for a different aa proline
The substitution of an incorrect amino acid is called a missense mutation

52
Q

What disease is an example of a missense mutation?

A

Sickle cell anemia

53
Q

Describe sickle cell anemia

A

Missense mutation in B globin gene in which GAG (glutamate) is changed to GTG (valine) giving rise to HbS
Alters conformation of deoxy Hb which aggregates and forms rod like structures
Deformation of RBCs into sickle shape
Poor O2 carrying capacity and tends to clog capillaries, thus restricting blood supply
High prevalence in African Americans
sx: anemia, pain, frequent infections and delayed growth/puberty

54
Q

What is a nonsense mutation?

A

Codon containing changed base may become a termination codon
Ex. If serine codon UCA is given a different second base A to become UAA -> new codon causes termination of translation
Production of truncated protein occurs

55
Q

What disease is due to a nonsense mutation?

A

Beta thalassemia

56
Q

What is beta thalassemia?

A

Lack of production of B globin protein due to nonsense mutations
Homozygous mutation of splice sites + nonsense mutations that introduce premature stop signals at codons

57
Q

What is a frameshift mutation?

A

If 1-2 nts are deleted or added to the coding region
Alters the reading frame
Results in a product with a radically different AA sequence or truncated product

58
Q

What disease is caused by a frameshift mutation?

A

Cystic fibrosis

59
Q

What is cystic fibrosis?

A

Most commonly caused by deletion of 3 nts from coding region -> loss of The in the CFTR protein (in 70% of pt)
Mutation prevents normal folding of CFTR protein which normally functions as Cl channel in epithelium
Production of sticky thick secretions in lungs and pancreas leading to lung damage and GI deficiencies

60
Q

What are epigenetics?

A

Changes that do not affect DNA sequence
Affected by environment
Alterations in gene expression are stably inherited

61
Q

What are the two main types of epigenetic modification?

A

Direct DNA methylation of the gene

Histone modification by acetylation and deacetylation

62
Q

What is the major site of DNA methylation in mammals?

A

A cytosine base in DNA (especially the 5’ cytosine adjacent to gaunosine base) because they tend to cluster close to the promoter regions of the gene
Thought to cause steric hindrance to binding of TFs

63
Q

What is imprinting?

A

Silencing of genes on chromosomes by methylated them

Genes are said to be imprinted depending on which parent contributed that gene

64
Q

What is Fragile X syndrome (FXS)?

A

Example of imprinting
Caused by mutation of fragile X mental retardation I (FMRI) gene on the X chromosome
Addition of CGG tri-nt repeats causing hyermethylation inactivating FMRI
sx: intellectual disability, problems with social interaction, delayed speech, physical features including long and narrow face, large ears, flexible fingers and large testicles

65
Q

What is histone modification?

A

Making DNA more or less accessible to TFs
Lysine residue acetylation weakens the DNA-histone interactions and makes the DNA more accessible to factors needed for transcription
Acetylation vs deacetylation

66
Q

What is histone acetylation catalyzed by?

A

Histone acetyltransferases or HATs

Associated with transcriptional activation

67
Q

What enzyme catalyzes histone deacetylation?

A 
histone deacetylase (HDAC) 
Associated with gene silencing
68
Q

Describe the role epigenetic plays in cancer

A

Silencing tumor suppression genes causes cancer
ex. p16 silenced in many tumors
Cancer cells may use epigenetic mods for therapy resistance
But epigenetics can also be a target for cancer therapy

SFM Exam 2 (25 decks)

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