M2C: Genes And Chromosomes

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genome

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genetic complement of an organism

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chromosome

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a single molecule DNA and the associated proteins, all together which make up a genome

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prokaryotic genome

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small: 10^5-10^6 bps
simple: linear and circular (usually)
typically one chromosome and one copy of that chromosome

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eukaryotic genome

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large: 10^7 (yeast) -10^9 (human) bps in nucleus
complex: many introns (junk) DNA. 95% of human genome.
Haploid in germ cells, diploid in other cells (in sexual species)
Organized into multiple linear chromosomes (16 in yeast, 24 in humans).
Primary genome in nucleus, small genome in organelles.

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repetitive DNA sequences

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Can span thousands of bps. Usually between genes. Some repetitive regions have special function (which?).

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Satellites (size)

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Repetitive sections of DNA. Can range from a single nucleotide to hundreds of nucleotides. 3 nucleotides of smaller is a microsatellite.

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VNTR

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Variable Number Tandem Repeats: regions where number of nucleotide repeats vary between individuals.

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Microsatellite instability

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number of copies can increase or decrease after replication

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Huntington's Chorea

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Caused by expansion of a poly-glutamine (CAG) encoding stretch of a gene. 35 = Huntington's Chorea, <40>500 = severe/early onset.

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Chromatid

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During mitosis, 2 copies of each chromosome replicate (to make 4). Each of the copies (and originals) are called chromatids.

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Centromeres

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Chromatids are joined at a specific point along the length of the chromosome. Centromere is this point. Where the kinetochore attaches.

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Kinetochore

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A protein machine that mediates:
duplicated chromosomes to allign on the mid-cell plane.
Chromatids are split (from centromere point).
Chromatids are dragged to poles of cell.

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Cytokinesis

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Physical division of cell

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Aneuploid

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Cell with the wrong number of chromosomes. Caused by improper segregation of cell at cytokinesis. Commonly causes disease and cancer.

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Centromere structure

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In multicellular eukaryotes, centromeres typically include several hundred thousand bps and include the alpha satellite repetitive region. While their individual structure varies, they are interchangable between chromosomes.

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Histone H3 varient CENP-A

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Nucleosomes in centromeres have this. It helps direct kinetochore attachement.

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Telomeres

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Short repeated sequence at the ends of linear chromosomes. In humans, 500-2000 repeats of GGGTTA in each telomere.

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Why we need Telomeres

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Due to lack of further primer activity at ends of chromosomes, at each replication, small end region is unreplicated. Telomeres exist so that genes near the ends of chromosomes remain intact. DNA ends are also prone to degredation if left "uncapped". Could fuse with other chromosomes for "repair" leading to improper replication and division. Failing a "check point" could also lead to cell death.

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Telomerase and the "fix" to the replication problem

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Telomerase is an enzyme that adds telomeric sequence at each replication of the chromasome (in early cell growth). Remedies the "replication problem" by adding telomeric sequence to un-replicatable region at end of chromasome.

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How telomerase works

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Works like regular DNA polymerase (3'-5')except does not need DNA template strand to direct synthesis. Uses intrinsic RNA strand to synthesize GGGTTA sequence only (UAACCCUAA...).

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T-loops

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Single stranded region of telomere loops back and inserts into double helix region of telomere. Protects end region from degredation or "repair".

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TRF-2

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Telomere Repeat Binding Factor-2. Mediates telomere loop formation.

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Telomeres and proliferative capacity

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Short telomeres = limited proliferative capacity.
Long telomeres = greater proliferative capacity

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Telomeres and aging

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Cells produce telomerase only to a point. When telomerase production ends, number of chromosome replications is limited. When telomere shortens to a certain point, senescence occurs and cellular replication ends.

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Senescence

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The end of cellular replication caused by the telomere shortening to a certain point. Senescence is important in aging.

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Crisis

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When a telomere shortens to a point where cell can no longer survive.

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Cancer and Crisis

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During crisis, most cells are killed, some learn how to continue to express telomerase, and therefore, their telomeres do not shorten and they continue to replicate.

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DNA compaction problem

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Human genome is two meters long and must fit into an area 6 microns in diameter. Also is prone to breaking and entanglement unless well packaged.

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Nucleosome

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Core subunit of chromosome packing.

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Nucleosome structure

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Contains core octamer of to of each Histone proteins (H2A, H2B, H3, and H4). Positive charge on outside of histones interacts with the negative charge on the outside of the DNA. DNA wraps almost twice around octamer. Whole package is ~20nm wide.

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Histone

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Small globular proteins with an extended tail rich in basic aa/positive charges.

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H1 Histone

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Linker Histone. Mediates packing of adjacent nucleosomes.

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Higher order nucleosome packing

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Nucleosomes are packed into 30nm-wide fibers (~6 nucleosomes/turn). A helical structure.

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Nucloesome packaging and transcription.

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Cells dynamically regulate chromatin packaging. Condensing for easier segregation during cellular division and loosening certain parts at certain times for easier transcription and replication.

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Euchromatin

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Very loosely packaged chromatin during non-replicating stage.

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Heterochromatin

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Areas of chromatin that do not include much transcriptional areas. Tend to stay tightly compacted. Often include highly repetative regions, centromeres and telomeres. Also areas that are not necessary to transcribe in a particular cell type.

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Remodeling

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The ability to adjust nucleosome positioning in chromatin.

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Remodeling complexes

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Multi-protein complexes use energy from ATP to adjust nucleosome positioning. Also used for creating nucleosomes "de novo" in recently replicated DNA.

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How nucleosomes are remodeled.

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Remodeling complexes use modify histones with histone modifying enzymes to change strength of positive parts of histones relation to negative parts of DNA.

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Histone Modifying Enzymes

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Histone acetylases, de-acetylases. Histone methylases. Histone kinases.

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H2AZ

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Replaces H2A histone in regions that are typically stable heterochromatic.