Introduction to Nucleic Acids, DNA, Chromatin and Chromosome Structure Flashcards by Joel Glotfelty

Store and express genetic information and transmit it from one generation to the next

-Confer individuality

Nucleic Acids (DNA and RNA)

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Joins DNA segments to form hybrid molecules

Ex: Chromosome crossing over during meiosis and the diversity of B cells

Recombination

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Every cell contains the exact same DNA, but the diversity comes from the

Expression of that DNA

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What nucleotide component actually carries the genetic information?

The base

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How can we combat the bacteria Salmonella typhimurium?

Inactivtion of DNA adenine methylase (dam)

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Blocks expression of virulent genes, prevents disease development, and induces an immune response

Inactivation of dam

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Incorporated in the DNA during replication and block further DNA synthesis

-does not significantly affect the host cell metabolism

Nucleoside analogs

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Hydrolyze phosphodiester bonds

Nucleases

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What is the most common form of DNA?

B DNA

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States that there must be equal amounts of purines and pyrimidines in the double-stranded DNA

Chargaff’s rule

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Each diploid cell contains how many chromosomes?

46 (6ft of DNA)

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Linear or circular B-form double helix

Relaxed conformation

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Has fewer helical turns than the relaxed B-form DNA double-helix

-classified as anything less than 10 helical turns

Negative supercoil

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Negative supercoils are energetically favored. The energy needed for strand separation is stored in

Supercoils

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Force the eukaryotic DNA to wrap around them and generate a negative supercoil

Histones

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Change the tertiary structure of DNA by transiently breaking one or both DNA strands, passing the strands through the break, and rejoining the strands

-induces “swivel points” in the DNA helix

Topoisomerases

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Why do we need topoisomerases?

Positive supercoiling is too much tension, so topoisomerases come in and release the tension

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How are topoisomerases able to work?

They have nuclease and ligase activity

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What makes DNA gyrase (a Topo II) unusual?

It can induce negative super coils into relaxed DNA

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Why is inhibition of DNA gyrase a good strategy for antibiotics?

It inhibits bacterial DNA syntheis, and since Eukaryotes do not have DNA gyrase, there are no side effects for humans

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Inhibition of eukaryotic Topoisomerases is used in cancer treatment, this has signigicant side effects because it will

Lead to cell death

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DNA is associated with non-histone proteins and condensed into a non-membrane bound nucleoid in

Prokaryotes

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DNA is associated with histone and non-histone proteins and is condensed into a nucleoprotein complex called chromatin in

Eukaryotes

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Chromatin is arranged in repeating units (like beads on a string) called

Nucleosomes

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What is the structure of a Nucleosome

1. ) Core: made up of DNA supercoils and histones | 2. ) DNA spacer

20-80 bp of DNA between cores -binds H1

DNA spacer

The regional compaction of chromatin is affected by

Histone modifications

As soon as DNA replication is completed, one histone H1 binds the spacer DNA which promotes

Tight packing (Solenoid)

In prokaryotes, replication is initiated by strand separation at a location rich in A:T base pairs, called the

Origin of replication

DNA unwinding is catalyzed by DNA helicase within the

Pre-priming complex

Bind DNA cooperatively to keep the single strands apart and protect them from nucleases

Single-strand DNA-binding proteins (SSBs)

What would be the affect of an inhibitor of Helicase?

Inhibited progression of DNA replication

DNA polymerase can not initiate synthesis on a totally single-stranded template. As a result, it requires an

RNA primer

Can replaced mismatched nucleotides that escaped proofreading after DNA replication

Mismatch Repair (MMR) pathway

Has 5' to 3' exonuclease activity, which it uses to remove RNA primers from Okazaki fragments before it fills in the gap with DNA

DNA polymerase I

ATP dependent enzyme that covalently joins Okazaki fragments

DNA ligase

Contains primase and initiates syntheses on the leading and lagging strand in eukaryotic replication

DNA polymerase α

DNA polymerase α has no

Exonuclease activity

Responsible for DNA replication on the lagging strand in eukaryotes - associates with proliferating cell nuclear antigen (PCNA) - has 3' to 5' exonuclease activity

DNA Polymerase δ

Responsible for DNA synthesis on the leading strand in eukaryotes - associates with processivity factor of PCNA - has 3' to 5' exonuclease activity

DNA Polymerase ε

Displaces the 5' ends of primers from Okazaki fragments

DNA Polymerase δ

Consist of short non-coding G-rich DNA repeats (TTAGGG) and associated proteins - form T loops - Located at ends of linear chromosomes

Telomeres

Protect the ends of DNA from recognition as broken DNA and degredation

Telomeres

A ribonucleoprotein complex that adds short G-rich DNA repeats (TTAGGG) to the single stranded 3'-ends of linear chromosomes

Telomerase

Uses it's RNA component to extend the parent strand and then its protein component (with reverse transcriptase activity) to synthesize DNA

Telomerase

Implicated in cell aging and cancer

Telomerase

In most somatic cells, telomerase is inactive. So to prevent telomere shortening and eventual chromosome end-to-end fusion, p53 induces

Cell growth arrest (stops cell from replication)

Can limit human cancer cell proliferation

Telomerae inhibitors

Inherited disease caused by reduced Telomerase activity -affects precursor cells in highly proliferative tissues

Dyskeratosis Congenita

Patients with Dyskeratosis Congenita generally die from

Bone marrow failure

Rare inherited condition that shows accelerated telomere shortening -Patients generally die from a myocardial infarction before age 20

Hutchinson-Gilford Progeria

Incorporation of an incorrect nucleotide or of an extra nucleotide -None of the nucleotides are defective

Mismatch

When there is a damaged base, the Base Excision Repair (BER) pathway is activated, what does it do?

Damage base removed, sugar backbone is cut and sugar phosphate residue is removed. Gap is pilled by DNA polymerase

Repair proteins, recognize mismatches, and distinguish the newly synthesized strand with the error from the parental strand

Mismatch Repair pathway (MMR)

In prokaryotes, a mismatched DNA is recognized because it is

Not immediately methylated

How does MMR work?

Helicase and exonuclease remove the mismtched DNA and DNA poylmerase III fills the gap

90% of lynch ryndrome patients have mutations in

MSH2 or MLH1 (MMR proteins)

Reactive oxygen species (ROS), by-products of cellular metabolism and certain chemicals can cause damage to the bases in our DNA. This damage is corrected by the

Base Excision Repair pathway (BER)

Mutation that interfere with BER lead to a high risk of

Colon cancer

Premature aging disease caused by the inhibition of WRN helicase, which is involved in the BER

Werners Syndrome

Cigarette smoke contains carcinogens. Once oxidized, these compounds covalently bind to G residues in the DNA of lung cells and distort the helix. What pathway would be used to fix this?

Nucleotide excision repair pathway

The only mechanism that removes bulky DNA adduct

Nucleotide Excision repair

Used if adduct is in a transcriptionally inactive region of DNA -Highly associated with cancer

Global Genomic NER

Used if adduct is in a transcriptionally active region of DNA -associated with CNS disorders

Transcription-coupled NER

Xeroderma pigmentosum, a hereditary disorder resulting from defects in global genomic NER, results in extreme

Solar sensitivity and highly increased risk of skin cancer

Adducts in transcriptionally active regions of DNA block the progression of -Halts gene transcription

RNA polymerase II

Hereditary developmental and neurological disorder associated it defects in TC-NER where there are mutations in CSA or CSB which affects recognition of stalled RNA polymerase II

Cockayne syndrome

Unlike patients with Xeroderma pigmentosum, patients with Cockayne Syndrome are not at increased risk for

Skin cancer

Repairs errors commonly caused by oxidative damage that results in a break in one strand of the DNA that is typically missing a single nucleotide

Single-strand break repair pathway

A single strand break is first recognized by -Recruits XRCC1

PARP-1 -Poly(ADP-ribose) polymerase 1

Restores the proper 3' OH and 5' phosphates of the damaged DNA which enables beta-polymerase to insert the missing nucleotide

Aprataxin (APTX)

Ataxia Oculomotor Apraxia is an autosomal recessive spinocerebellar ataxia syndrome caused by mutation in the

APTX gene

Severely compromise genome stability and lead to loss of chromosome fragments in mitosis -Cause cancer due to joining of the wrong ends

Double-stranded breaks

The major pathway to repair double-stranded breaks. Rejoins what remains of two broken DNA ends - Does not require any sequence homology - error prone

Non-homologous end-joining (NHEJ)

In NHEJ, frayed ends are removed (if needed) by the endonuclease activity of

DNA-PKcs:Artemis

Information on the homologous sequence is used to repair the broken DNA -requires alignment of highly homologous DNA molecules

Homologous recombination

Results in no change in DNA sequence -error free

Homologous recombination

Mutation in homologous recombination proteins BRCA1 or BRCA2 leads to an 80% lifetime risk of developing

Breast or Ovarian Cancer

Tumors in BRCA carriers are more sensitive to -due to defects in DSB HR repair

Ionizing radiation

Ataxia Telangiectasia is an autosomal recessive disorder that has a propensity to develop lymphoid cancer. It is associated with a mutation in a protein that is normally activated by double stranded breaks. The protein signals the cell-cycle check point to slow the cell cycle. What is this protein?

AMT