Genomic Regulation

Question 1

• Euchromatin

Answer 1

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

Question 2

• Heterochromatin

Answer 2

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

Question 3

• Histone Acetylation

Answer 3

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

Question 4

• Histone Methylation

Answer 4

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

Question 5

• Phosphorylation-

Answer 5

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

Question 6

• Helicase

Answer 6

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

Question 7

• Topoisomerase

Answer 7

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

Question 8

Nucleoside analog inhibitors (Correlation box)

Answer 8

• 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)

Question 9

i. Ionizing radiation (X-rays)

Answer 9

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

Question 10

ii. Non-ionizing (UV light)

Answer 10

• 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)

Question 11

iii. Spontaneous Mutation

Answer 11

• 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

Question 12

i. Direct repair

Answer 12

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

Question 13

ii. Base excision repair

Answer 13

• Type of damage repaired: Single-base mismatch

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

Question 14

iii. Nucleotide excision repair

Answer 14

• 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

Question 15

iv. Mismatch repair

Answer 15

• 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

Question 16

v. Recombination repair

Answer 16

• 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

Question 17

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

Answer 17

• Colon cancer

* Mismatch repair

Question 18

ii. Xeroderma pigmentosum

Answer 18

• Skin cancer, UV sensitivity, neurological abnormalities

* Nucleotide excision-repair

Question 19

ii. Hereditary nonpolyposis colorectal cancer

Answer 19

• 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

Question 20

iii. Cockayne syndrome

Answer 20

• 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

Question 21

Epigenetics

Answer 21

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

Question 22

i. Methylation

Answer 22

• 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

Question 23

• HATs

Answer 23

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

Question 24

• HDACs

Answer 24

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)