Hoá sinh 1

Chapter 19
Eukaryotic genomes: organization, regulation and evolution
http://www.studiodaily.com/main/searchlist/6850.html

“The Inner life of the Cell”
Gene expression…
Is altered in response to environmental changes, both internal and external
Is influenced by the structure of chromatin
Heterochromatin is highly compacted and is not transcribed
Euchromatin is less compacted and available for transcription
Is most often regulated at the transcription stage
Differential gene expression (cell differentiation) is the result of genes being turned “on” or “off” in different cells having the same genome
Only 1.5% of human DNA codes for proteins
Chromatin structure….
Eukaryotic DNA associates with many histone proteins that form complex structures – the mass of histones = the mass of DNA
Histones – highly conserved, small, basic proteins that shape the 1st level of chromatin structure:
The high [ ]’s of arganine and lysine make them +ly charged
Of the 5 types (H1,H2A,H2B,H3,H4) all but H1 are found in the nucleosome, the basic unit of DNA packing
Are evolutionarily conserved
Only leave DNA briefly during replication
Interphase chromatin is attached to the nuclear lamina to keep chromosomes from tangling
Eukaryotic DNA structure
DNA + histones form nucleosomes (10nm fiber)
Nucleosomes coil to form chromatin fiber (30nm fiber)
30nm fiber folds into looped domains (300nm fiber)
Chromatin condenses further to form the metaphase chromosome (highly compacted 1400 nm)
CONTROL POINTS in eukaryotic gene expression:
Regulation of chromatin structure: histone acetylation and DNA methylation
Transcription of the gene: transcription initiation
RNA Processing: alternative RNA splicing
mRNA export:
mRNA degradation: polyA tail, miRNA, RNAi
Translation of mRNA: regulatory proteins block initiation of translation
Polypeptide processing: cleavage, modification and transport
Protein Degradation: ubiquitin/proteasome activity




Stages in which eukaryotic gene expression can be regulated are represented by the colored boxes
Regulation of chromatin structure:
Histone modification – acetyl groups added to histone tails relax chromatin and promote transcription
DNA methylation can inactivate genes and be inherited by offspring– genomic imprinting works this way!
Control of gene expression in eukaryotes: an overview
http://highered.mcgraw-hill.com/olc/dl/120080/bio31.swf
The eukaryotic gene consists of
the gene + RNA polymerase + a promoter
Control elements – non-coding DNA that regulates transcription by binding to certain proteins. Distal elements called enhancers are very important
Transcription factors:
General transcription factors result in low RNA production
Specific transcription factors can promote high levels of transcription. They may be:
Activators – protein that stimulates transcription
Repressors – proteins that inhibit gene expression
Activators and repressors may alter chromatin structure, thereby further influencing gene expression
Transcription of the gene: regulation of initiation
Prokaryotes have operons to control expression of genes with related functions…what about eukaryotes?
Functionally related eukaryotic genes are co-expressed because they have the same control elements that are activated by the same chemical signals
Regulation of transcription
http://wps.aw.com/bc_campbell_biology_7/0,9854,1704975-,00.html
RNA processing:
Alternative RNA splicing can generate different mRNA molecules from the same primary transcript – organisms can produce more than 1 polypeptide from a single gene!
The mRNA transcript:
mRNA degradation:
Eukaryotic mRNA can have a survival time measured in weeks…how is it degraded?
Shortening of the poly-A tail and removal of the 5’cap allows nucleases to degrade mRNA
microRNA’s can degrade mRNA or block its translation (called RNA interference)
mRNA degradation:
mRNA translation
Initiation of translation can be blocked by regulatory proteins that bind to the UTR’s and block the attachment of ribosomes to the mRNA
Polypeptide processing:
Any interference in the processing of the polypeptide can alter gene expression. Polypeptides are processed via
Cleavage
Chemical modifications
Protein transport to its target destination
Degradation of protein:
The lifespan of a protein varies and is strictly regulated by other proteins
Proteins tagged with ubiquitin are recognized by proteosomes and degraded
Protein degradation:
A review of gene expression: prokaryotes vs eukaryotes
http://highered.mcgraw-hill.com/olc/dl/120077/bio25.swf
Gene expression:
prokaryotic eukaryotic
Small genome, no specialization
Most of their DNA codes for protein or RNA’s, very little “junk”
Genome = DNA + few proteins in simple arrangement
RNA processing not an option for controlling gene expression
mRNA has a short life span (minutes)





Both alter gene expression in response to environment; in both, transcription initiation is the most important control point
Larger genome, cell specialization
Most of the DNA does not code for protein or RNA’s
Genome = DNA w/many proteins in complex arrangement
RNA processing allows for several opportunities to regulate genes
mRNA is long lived (days to months)

Cancer results from genetic changes that affect cell cycle control

It is a disease in which cells escape control methods that normally regulate cell growth and division
The agents of change can be random spontaneous mutations or carcinogens
Cancer-causing genes, oncogenes, were originally discovered in retroviruses
Proto-oncogenes:
Proto-oncogenes code for proteins that stimulate normal cell growth and division They may turn into oncogenes by:
Translocation/transposition within the genome
Gene amplification
Point mutations within a control element or the gene that may lead to a protein that is more active or longer lived
Proto-oncogenes
Tumor-suppressor genes
Tumor-suppressor genes encode for proteins that help prevent uncontrolled cell division. They may function to:
Repair damaged DNA
Control cell adhesion
Act as components of cell-signaling pathways that inhibit the cell cycle
A mutation in a tumor suppressor gene reduces the activity of its protein product, leads to excessive cell division and potentially cancer
Some proteins encoded by proto-oncogenes and tumor-suppressor genes are components of cell signaling pathways
The Ras proto-oncogene (G protein) is part of a cell cycle stimulating pathway. A mutation making this pathway abnormally active could result in cancer
The product of the p53 gene (p53 protein) inhibits the cell cycle and allows time for DNA repair mechanisms to operate. Deficiencies in this cell cycle inhibiting pathway could promote cancer
Control of the cell cycle: p53 and rb
http://highered.mcgraw-hill.com/sites/0072437316/student_view0/chapter20/animations.html#
The multistep model for cancer development:
Cancer results from an accumulation of mutations, not just one
Usually there is the presence of one active oncogene and the mutation of several tumor-suppressor genes
Certain viruses can promote cancer by insertion of viral DNA into a cells genome
Individuals who inherit a mutant oncogene or tumor-suppressor allele have an increased risk of developing cancer
Eukaryotic genomes have many noncoding DNA sequences in addition to genes
Eukaryotes have fewer genes/DNA length than do prokaryotese
Most of the DNA is noncoding (98.5%)
Most intergenic DNA is repetitive DNA in the form of transposable elements and related sequences (44%)
There are 2 types of transposable elements:
Transposons and retrotransposons
Transposable elements:
Transposons:
Move within a genome via a DNA intermediate
Can move via:
Cut-and-paste methods
Copy and paste methods
Retrotransposons:
Move within a genome via an RNA intermediate
This is the most prevalent type
Simple sequence DNA
Short, noncoding DNA sequences
Tandemly repeated
Prominent in centromeres and telomeres
Play a structural role in the chromosome
Multigene families:
Collections of identical or very similar genes,
A multigene family is a member of a family of related proteins encoded by a set of similar genes. Multigene families are believed to have arisen by duplication and variation of a single ancestral gene. Examples of multigene families include those that encode the actins, hemoglobins, immunoglobulins, and histones.
The evolution of the Genome - a history of mutation!
Polyploidy! A duplication of chromosome sets. One set functions normally, the other is free to diverge
Duplication of individual DNA segments or genes which may then diverge to create new genes and gene products
Rearrangement of gene parts:
Exon duplication
Exon shuffling
The use of transposable elements that promote recombination, disrupt genes, or carry genes to new locations also contributes to genome evolution