Cell as a Unit of Health and Disease Flashcards
study of of cellular abnormalities.
Modern Pathology
variously function as enzymes, structural components, and signaling molecules and are used to assemble and maintain all of the cells in the body.
Genome Proteins-encoding Genes
dispersed, transcriptionally active
euchromatin
densely packed, transcriptionally inactive
heterochromatin
centromeres act as the locus for the formation of a ____________ that regulates chromosome segregation at metaphase.
kinetochore protein complex
repetitive nucleotide sequences that cap the termini of chromatids and permit repeated chromosomal replication without loss of DNA at the chromosome ends.
The telomeres
chromatids are organized into short _______ (“ next letter in the alphabet ”) arms. The characteristic banding pattern of chromatids has been attributed to relative GC content (less GC content in bands relative to interbands), with genes tending to localize to interband regions.
“P” (“ petite ”) and long “Q”
DNA wound around octameric histone cores
nucleosomes
Promoters are noncoding regions of DNA that initiate gene transcription are located at?
they are on the same strand and upstream of their associated gene.
The intronic sequences are subsequently spliced out of the _____ to produce the definitive message that is translated into protein—without the 3′- and 5′-untranslated regions (UTR).
pre-mRNA
perhaps most, of the genetic variations ( polymorphisms ) associated with diseases are located in _________ regions of the genome.
non–protein-coding
TRUE OF FALSE:
variation in gene regulation may prove to be more important in disease causation than structural changes in specific proteins.
TRUE
Thus, person-to-person variation, including differential susceptibility to diseases and in response to environmental agents and drugs, is encoded in _____of our DNA.
less than 0.5%
The two most common forms of DNA variation in the human genome are?
single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs)
are variants at single nucleotide positions and are almost always biallelic
single-nucleotide polymorphisms (SNPs)
SNPs occur across the genome—within?
exons, introns, intergenic regions, and coding regions.
regions. Overall, about 1% of SNPs occur in
coding regions,
TRUE OR FALSE:
In other instances, the SNP may be a “neutral” variant that has no effect on gene function or carrier phenotype.
TRUE
TRUE OR FALSE:
In other instances, the SNP may be a “neutral” variant that has no effect on gene function or carrier phenotype.
TRUE
even ________ may be useful markers if they happen to be co-inherited with a disease-associated gene as a result of physical proximity.
“neutral” SNPs
other words, the SNP and the causative genetic factor are in
linkage disequilibrium.
CNVs are a more recently identified form of genetic variation consisting of different numbers of large contiguous stretches of DNA from 1000 base pairs to millions of base pairs.
copy number variations - CNVs
are responsible for between 5 and 24 million base pairs of sequence difference between any two individuals.
CNVs
TRUE OR FALSE:
We currently know much less about CNVs than SNPs, therefore their influence on disease susceptibility is less established.
TRUE
heritable changes in gene expression that are not caused by alterations in DNA sequence.
epigenetics,
Such cell type-specific differences in DNA transcription and translation depend on _______ (literally, factors that are “above genetics”)
epigenetic factors
consist of DNA segments 147 base pairs long that are wrapped around a central core structure of highly conserved low molecular weight proteins called histones
Nucleosomes
a central core structure of highly conserved low molecular weight proteins called ___
histones
The resulting DNA-histone complex resembles a series of beads joined by short DNA linkers and is generically called
chromatin
nuclear chromatin exists in two basic forms: (1) cytochemically dense and transcriptionally inactive ________ and (2) cytochemically dispersed and transcriptionally active _______
heterochromatin ; euchromatin
______ can reposition nucleosomes on DNA, exposing (or obscuring) gene regulatory elements such as promoters. “
chromatin remodeling complexes c
carry out more than 70 different histone modifications generically denoted as marks
Chromatin writer” complexes
Actively transcribed genes in euchromatin are associated with ________ that make the DNA accessible to RNA polymerases.
histone marks
______ have histone marks that enable DNA compaction into heterochromatin.
inactive genes
Histone marks are reversible through the activity of “chromatin erasers.”
Histone marks are reversible through the activity of
“chromatin erasers.”
binding histones that bear particular marks and thereby regulating gene expression.
“chromatin readers,”
Both lysines and arginines can be methylated by specific writer enzymes; in particular, methylation of lysine residues in histones may be associated with either transcriptional activation or repression, depending on the histone residue that is “marked”.
Histone methylation
. Lysine residues are acetylated by histone acetyl transferases (HAT), whose modifications tend to open up the chromatin and increase transcription. In turn, these changes can be reversed by histone deacetylases (HDAC), leading to chromatin condensation.
Histone acetylation
Serine residues can be modified by phosphorylation; depending on the specific residue, the DNA may be opened up for transcription or condensed to become inactive.
Serine residues can be modified by phosphorylation; depending on the specific residue, the DNA may be opened up for transcription or condensed to become inactive.
Histone phosphorylation .
________ High levels of DNA methylation in gene regulatory elements typically result in transcriptional silencing. Like histone modifications, DNA methylation is tightly regulated by methyltransferases, demethylating enzymes, and methylated-DNA-binding proteins.
DNA methylation.
__________- Much less is known about these proteins, which are believed to bind to noncoding regions and control long-range looping of DNA, which is important in regulating the spatial relationships between gene enhancers and promoters that control gene expression.
Chromatin organizing factors.
histone H1 sits on the_____ between nucleosomes and helps stabilizes the overall chromatin architecture.
20-80 nucleotide linker DNA
The histone subunits are _____- charged, thus allowing the compaction of the negatively charged DNA.
positively charged
Certain marks such as _______ “open up” the chromatin structure
histone acetylation
tends to condense the DNA and leads to gene silencing.
methylation of particular histone residues,
many epigenetic alterations (e.g., histone acetylation and DNA methylation) are ____________
reversible and are amenable to therapeutic intervention
many epigenetic alterations (e.g., histone acetylation and DNA methylation) are ____________
reversible and are amenable to therapeutic intervention
are already being tested in the treatment of various forms of cancer.
HDAC inhibitors and DNA methylation inhibitors
encoded by genes that are transcribed but not translated.
noncoding RNAs.
_________ do not encode proteins; instead, they function primarily to modulate the translation of target mRNAs into their corresponding proteins.
The miRNAs
_____ by miRNA is a fundamental and well-conserved mechanism of gene regulation present in all eukaryotes (plants and animals)
Posttranscriptional silencing of gene expression
By current estimates, the human genome encodes approximately _______ , some _________ the number of protein-coding genes.
1000 miRNA genes ; 20-fold less than
By current estimates, the human genome encodes approximately _______ , some _________ the number of protein-coding genes.
1000 miRNA genes ; 20-fold less than
generates mature single-stranded miRNAs of 21 to 30 nucleotides that are associated with a multiprotein aggregate called RNA-induced silencing complex
enzyme DICER.
Subsequent base pairing between the miRNA strand and its target mRNA directs the ____ to either induce mRNA cleavage or repress its translation.
RISC
All mRNAs contain a so-called ______ in their 3′ untranslated region (UTR) that determines the specificity of miRNA binding and gene silencing. In this way, the target mRNA is posttranscriptionally silenced
seed sequence
are short RNA sequences that can be introduced experimentally into cells. These serves as substrates for Dicer and interact with the RISC complex in a mannaer analogous to endogenous miRNAs.
Small interfering RNAs (siRNAs)
Synthetic siRNAs targeted against specific mRNA species have become useful laboratory tools to study gene function (so-called _____);
knockdown technology
they are also being developed as possible therapeutic agents to silence pathogenic genes, such as oncogenes involved in neoplastic transformation.
Synthetic siRNAs targeted against specific mRNA
number of lncRNAs may exceed coding mRNAs by ___.
10- to 20-fold
transcribed from the X chromosome and plays an essential role in physiologic X chromosome inactivation.
XIST
_____itself escapes X inactivation, but forms a repressive “cloak” on the X chromosome from which it is transcribed, resulting in gene silencing.
XIST
can facilitate transcription factor binding and thus promote gene activation.
(lncRNAs)
can preemptively bind transcription factors and thus prevent gene transcription.
lncRNAs
may act as scaffolding to stabilize secondary or tertiary structures and/or multi-subunit complexes that influence general chromatin architecture or gene activity.
lncRNAs
The viability and normal activity of cells depend on a variety of fundamental housekeeping functions that all differentiated cells must perform. These functions include:
protection from the environment, nutrient acquisition, communication, movement, renewal of senescent molecules, molecular catabolism , and energy generation
Many normal housekeeping functions are compartmentalized within____
membrane-bound intracellular organelles
_____ allows the creation of unique intracellular environments (e.g., low pH or high calcium) that may then selectively regulate the function of enzymes or metabolic pathways.
compartmentalization
New proteins destined for the plasma membrane or points beyond are synthesized in the __________
rough endoplasmic reticulum (RER)
New proteins destined for the plasma membrane or points beyond are synthesized in the rough endoplasmic reticulum (RER) and physically assembled in the ___________
Golgi apparatus ;
proteins intended for the cytosol are synthesized on
free ribosomes.
may be abundant in certain cell types such as gonads and liver where it is used for steroid hormone and lipoprotein synthesis, as well as for the modification of hydrophobic compounds (for example, drugs) into water-soluble molecules for export.
Smooth endoplasmic reticulum (SER)
____ are intracellular organelles that contain degradative enzymes that permit the digestion of a wide-range of macromolecules, including proteins, polysaccharides, lipids, and nucleic acids.
Lysosomes
_______ are a specialized type of “grinder” that selectively chews up denatured proteins, releasing peptides. In some cases the peptides so generated can be presented in the context of class I major histocompatibility molecules
Proteasomes
_______ play a specialized role in the breakdown of fatty acids, generating hydrogen peroxide in this process.
Peroxisomes
shuttle internalized material to the appropriate intracellular sites or direct newly synthesized materials to the cell surface or targeted organelle.
Endosomal vesicles
Cell movement—both organelles and proteins within the cell, as well as movement of the cell in its environment—is accomplished through the
cytoskeleton
also serve as an important source of metabolic intermediates that are needed for anabolic metabolism; they are sites of synthesis of certain macromolecules (e.g., heme), and contain important sensors of cell damage that can initiate and regulate the process of programmed cell death.
mitochondria
fluid bilayers of amphipathic phospholipids with hydrophilic head groups that face the aqueous environment and hydrophobic lipid tails that interact with each other to form a barrier to passive diffusion of large or charged molecules
Plasma membranes
___ on the ____membrane leaflet can be phosphorylated, serving as an electrostatic scaffold for intracellular proteins
Phosphatidylinositol ; inner
is normally restricted to the inner face where it confers a negative charge involved in electrostatic protein interactions; however, when it flips to the extracellular face, which happens in cells undergoing apoptosis (programmed cell death), it becomes an “eat me” signal for phagocytes. In the special case of platelets, it serves as a cofactor in the clotting of blood.
Phosphatidylserine
___- are preferentially expressed on the extracellular face; glycolipids (and particularly gangliosides, with complex sugar linkages and terminal sialic acids that confer negative charges) are important in cell-cell and cell-matrix interactions, including inflammatory cell recruitment and sperm-egg interactions.
Glycolipids and sphingomyelin
___ are overrepresented in the outer leaflet, and ____ found on the inner leaflet;
phosphatidylcholine and sphingomyelin ; phosphatidylserine (negative charge) and phosphatidylethanolamine are predominantly
glycolipids occur only on the ___ face where they contribute to the extracellular glycocalyx.
outer
The phospholipid distribution within the membrane is asymmetric due to the activity of
flippases
certain membrane components have a predilection for association through horizontal interactions in the bilayer, which leads to the creation of distinct lipid domains known as
“lipid rafts.”
The plasma membrane is liberally studded with a variety of proteins and glycoproteins involved in __
(1) ion and metabolite transport
(2) fluid-phase and receptor-mediated uptake of macromolecules, and
(3) cell-ligand, cell-matrix, and cell-cell interactions.
Most proteins are _____, having one or more relatively hydrophobic α-helical segments that traverse the lipid bilayer.
integral or transmembrane proteins
TRUE OR FALSE:
Integral membrane proteins typically contain positively charged aminoacids in their cytoplasmic domains, which anchor the proteins to the negatively charged head groups of membrane phospholipids.
TRUE OR FALSE:
Integral membrane proteins typically contain positively charged aminoacids in their cytoplasmic domains, which anchor the proteins to the negatively charged head groups of membrane phospholipids.
TRUE
Proteins may be synthesized in the___ and posttranslationally attached to ___groups that insert into the ___ side of the plasma membrane.
cytosol ; prenyl ; cytosolic
Insertion into the membrane may occur through ___ anchors on the extracellular face of the membrane.
glycosylphosphatidylinositol (GPI)
____ may noncovalently associate with true transmembrane proteins.
Peripheral membrane proteins
Many plasma membrane proteins function together as large complexes; these may either be aggregated under the control of ____ or by ___ in the plasma membrane followed by complex formation in situ.
chaperone molecules in the RER ; lateral diffusion
unique membrane domains can be generated by the ___
interaction of proteins with cytoskeletal molecules or extracellular matrix.
