Genomic Regulation Flashcards

1
Q

• Euchromatin

A

Lightly packed form of chromatin, highly enriched in genes, often under active transcription, most active form of the genome

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2
Q

• Heterochromatin

A

very condensed, genetically inactive, contains few active genes, position effect: Activity of an active gene is silenced if moved near heterochromatin

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3
Q

• Histone Acetylation

A

modifying enzymes involved in histone acetylation are called histone acetyltransferases, promotes gene expression

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4
Q

• Histone Methylation

A

the transfer of one, two, or three methyl groups from S-adenosyl-L-methionine to lysine or arginine residues by histone methyltransferases

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5
Q

• Phosphorylation-

A

compaction is achieved by repeatedly folding chromatin fibers into a hierarchy or multiple loops and coils, accomplished by phospholylation of Histone H1

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6
Q

• Helicase

A

Unwinds DNA helix, bind and hydrolyze ATP, 1000bp/sec

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7
Q

• Topoisomerase

A

Relieves overwound supercoils, every 10 bp replicated corresponds to one turn, used as a target in anti-cancer drugs

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8
Q

Nucleoside analog inhibitors (Correlation box)

A
  • DNA synthesis involves the formation of 3’ to 5’ phosphodiester bonds, nucleoside analogs that lack the 3’-OH group act as drugs that inhibit DNA replication
  • Such nucleosides need to be converted to dNTPs before they can act as inhibitors of DNA polymerase
  • Ex: arabinosylcytosine (treatment of leukemia)
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9
Q

i. Ionizing radiation (X-rays)

A
  • 40 to 60 chemically distinct base damages
  • Direct strand breaks
  • DNA-protein cross-links
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10
Q

ii. Non-ionizing (UV light)

A
  • Inducing formation of a covalent linkage between adjacent pyrimidine bases
  • There are two outcomes
  • Pyrimidine cyclobutane dimers (common)
  • 6-4 covalent linkage of two pyrimidines (p53 cells)
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11
Q

iii. Spontaneous Mutation

A
  • Depurination: 5000 purine lost
  • Deamination: C to U change 100 bases/day
  • Adenine becomes hypoxanthine
  • Guanine becomes Xanthine
  • Cytosine becomes Uracil
  • Outcomes: DNA Replication Ensues or Base deletion or substitution
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12
Q

i. Direct repair

A
  • Type of damage repaired: Pyrimidine dimers, O6-methylguanine
  • Enzymes associated: DNA photolyase, Methylguanine methyltransferase
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13
Q

ii. Base excision repair

A
  • Type of damage repaired: Single-base mismatch

* Enzymes involved: DNA glycolases, AP endonuclease, AP lyase, DNA polymerase, DNA ligase

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14
Q

iii. Nucleotide excision repair

A
  • Type of Damage repaired: Chemical adducts (Nitrogen mustard, cisplatin, DMS, MMS) that distort DNA
  • Enzymes involved: NER protein complex, DNA polymerase, DNA ligase
  • Disease: Xeroderma pigmentosum
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15
Q

iv. Mismatch repair

A
  • Type of damage repaired: mismatched base in daughter strand
  • Enzymes involved: MER complex, helicase/endonuclease, DNA polymerase, DNA ligase
  • MutS binds while MutL scans for nick and triggers degradation of the nicked strand
  • Disorder: Hereditary nonpolyposis colorectal cancers
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16
Q

v. Recombination repair

A
  • Types of damage repaired: double-strand breaks
  • Enzymes involved: Exonucleases, DNA polymerase
  • Mechanism involved: damaged ends filled in and joined, some base pairs may be missing
  • Disorder: BRCA1/2 breast cancer
17
Q

i. MSH 2,3,6, MLH1, PMS2

A
  • Colon cancer

* Mismatch repair

18
Q

ii. Xeroderma pigmentosum

A
  • Skin cancer, UV sensitivity, neurological abnormalities

* Nucleotide excision-repair

19
Q

ii. Hereditary nonpolyposis colorectal cancer

A
  • Individuals with inherited mutations in one of the alleles of genes in the MER complex have an increased susceptibility
  • An acquired mutation in the remaining good copy of the gene would then render the MER system non-functional and allow for tumor development
20
Q

iii. Cockayne syndrome

A
  • Rare autosomal recessive disorder
  • Mutant genes involved are ERCC-6 and ERCC8 proteins
  • Developmental and neurological delay, photosensitivity
  • Death occurs in the first two decades of life
21
Q

Epigenetics

A

Mechanism for regulating gene activity independent of DNA sequence that determines which genes are turned on or off

22
Q

i. Methylation

A
  • Methyl groups added to the DNA molecules by methyl transferase enzymes
  • Changes the activity of a promoter region that mediates gene regulation
  • Represses gene transcription when at gene promoter
  • Essential for normal development
  • Alternations of DNA Methylation…important component of cancer development
  • Transcriptional silencing
  • Can be inherited by daughter cells following cell division
  • Occurs at the 5 position of pyrimidine ring of cystosine residues within CpG sites
  • Hypomethylation- chromosomal instability, loss of imprinting
  • Hypermethylation- associated with gene promoters, can arise secondary to gene (oncogene suppressor) silencing, might be a target for epigenetic therapy
23
Q

• HATs

A

acetylate core histones to neutralize the positively charged lysines and facilitate chromatin condensation, DNA repair, and gene transcripton (activation of expression)

24
Q

• HDACs

A

remove acetyl groups from the lysine on core histones and nonhistone proteins, cancer cells are very sensitive to HDACs inhibitors (valproic acid and vorinostat) (Repression of expression)