MTC Exam III part II Flashcards
histone tails
-19-39 aa N terminal tails extending from globular core
H2A and H2B also have flexible C-terminal tails
H1 phosphorylation: goal, enzyme, residues, etc.
goal: destabilization of a compacted chromatin region (activating)
H1 phosphorylation of Ser and Thr by H1 kinase enzyme. phosphorylate H1s bind HMG proteins instead. now, nucleosome is more accessible
core histone phosphorylation: where, enzymes, goals, etc.
Ser residues. neutralizes histones and promotes interactions with acetyl and methyl transferases
enzymes: MSK1, MSK2, RSK2 (map kinase cascade), IKK2
What enzyme catalyzes the dephosphorylation of a histone?
H1 phosphatase
Histone aceylation. residue? enzyme?
major covalent modification to change histone charge
acelation at the lys residues of histone tails
catalyzed by histone acetyl transferace (HAT)
acetyl group from acetyl CoA
de-acetylation of histones. enzyme(s)? regulation?
HDACs (histone deacetylation enzymes). HDACs regulated by phosphorylation by calmodulin-dependent protein kinases
Sir-2-like HDACs and sirtuins: deacetylation through and NAD-dependent process.
histone methylation: residues? enzymes? methyl donor?
histone tails, esp. H3 and H4, methylated at Lys or Arg.
catalyzed by histone methyltransferases with SAM as the donor.
methylation can occur mutliple times on the same residue: 3X with the lysine residue
General trends in histone methylation and activation vs. inactivation of transcription. how is activation/inactivation mediated?
Arg in H3 is activating
some lyseins on H3 are also activating. In these cases, methylation tends to reduce HDAC access.
But, methylation of H3 Lys 9 and 27 tends to be inactivating (mediated by HP1, which you know removes phosphatases and therefore downregulates transcription)
demethylating enzymes. what do they form?
E-N-methyl lysine demethylase: makes formaldehyde
peptidyl arginine demethylase: mutates arginines to citrullines
Poly(ADP-ribosylation) of histones
where? enzyme? effect?
ADP ribosyl transfered from NAD to a carboxyl group of glutamate or aspartate
catalyzed by poly ADPribosyl polymerase (PARP-1)
coactivator- poly-ADP ribosyl has a negative charge
What enzyme removes poly ADP ribosyl groups from histones?
poly (ADP ribose) glycohydrolase
ubiquitylation of histones: effect, reverse enzyme
mono ubiquitinyation leads to inactivation and silencing
reverse enzyme: E3 ubiqutin ligases
ATP-dependent nucleosome remodeling
what proteins? how do they work?
mechanical work of chromatin remodeling done by ATP-dependent motor proteins like SWI/SNF complex
this has tow actions:
sliding (moving nucleosome along DNA and structural alteration (partial or complete disruption of nucleosome)
CpG island
areas of CpG repeats in DNA of about 1kb in length. oftencoincide with promoter regions of housekeeping genes. In housekeeping genes, they are usually unmethylated; in other genes, they are usually methylated, esp. in L1 and Alu seq.
Rett Syndrome
defect of histone deacetylation
MeCP2 gene mutation (methyl CpG binding protien)
high transcriptional noise
abnormal neuro development
seen exclusively in girls: X-linked, and embryonic lethal in boys
maintenance DNA methytransferases
proteins that are critical for the stable transmission of epigenetic modification pattern from one cell generation to the next
immunodeficiency-centromeric instability facial syndrome (KF)
minor facial deformities, growth retardation, immunodeficiency, and weird chromosomal rearrangements
problem with maintenance DNA methyltransferases.
steps of heterochromatinization (4)
- Repressive factors gather at a silencer and cause deacetylation and/or methylation of H3K9
- HP1 recognizes and binds to nucleosomes methylated at H2K9
- HP1 recruits more methyltransferases, leading to spreading
- we have a condensed heterochromatin!
Prader-Willi: symptoms, inheritance, etc.
symptoms: neonatal hyptonia, hyperphagia (excessive hunger), obesity, hypogonadism, developmental disability
15q11.2 deletion
deletion is of paternal origin (P for paternal and prader willi)
Angelman: symptoms, inheritance, gene
unprovoked laughter, no speech, jerky hand movements, ataxic gait, seizures, hypopigmentation
15q11.2 deletion of the UBE3A gene
maternal origin
uniparental isodisomy vs. uniparental heterodisomy
isodisomy: 2 UPD alleles of same grandparental origin: duplication and transmission of a single chromosome
heterodisomy: 2 UDP alleles have different grandparental origin: both copies of the homologous chromosome of a single parent are transmitted
2 mechanisms for uniparental disomy
- fetrilization of a nullisomatic gamate by a disomatic gamate: requires 2 meiotic non-disjunction
- fetrilization of a disomatic gamate by a normal sperm, followed by trisomy rescue
deformation. examples
caused by mechanical pressure on a developing fetus (breech babies, twins, tumors, abnormal uterus). ex. jouint contractions, hip dislocation, some facial asymmetry
3 types of breech babies
frank: legs up toward head; butt out first
complete: legs near cervix
footling: foot out first
disruption. examples
interruption of normal developmental processes.
ex. amnion rupture. leads to the formation of small strands of amnion that encircle and constrict fetal structures: anular constrictions, amputations, or facial clefting
Treacher collins
pleitropic disorder characterized by craniofacial anomalies, dysplastic ears, deafness. single gene defect
three mechanisms for pleitropy
- gene plays a role in global or regional development processes (axis determination, for example)
- gene plays a role in critical pathways (Shh)
- gene plays a role in the devo of one tissue type, which goes on to develop many other systems (neural crest)
Potter sequence
NOT pleiotropy
renal anomoly leads to decreased urine production of the fetus leads to decreased amniotic fluid (oligohydramnios) leads to restricted limb development leads to congenital limb contracture, facial development problems, and skin defects.
external compression from oligohydramnios leads to lung undervelopment
this is an example of a malformation sequence
22q11 deletion syndrome
contiguous gene syndrome
conotruncal congenital heard disease, palatal defects, mandibular hypoplasia, hypoparathyroidism, immunodeficiency, craniofacial defects
2 examples of contiguous gene syndromes
22q11 deletion syndrome; WAGR (11p13 deletion)
non-allelic homologous recombination
homolgous recombination between two different chromosomes that each have a homologous sequence. leads to reciprocal translocations.
Crouzon syndrome. symptoms, mutation, inheritance pattern
craniosynostosis, ocular proptosis, shallow orbits, hypoplasia, hearing loss, possible mental deficiencies
FGFR2 defects
variable expression and non-penetrance
Ehlers-Danlos: general symptoms
skin yperextensibility and elasticity, abnormal would healing, joint hypermobility, hypotonia, fatigue, muscle cramps, mitral and tricuspid valve prolapse, aortic root dilation, etc
EDS III
subluxation, dislocations, chronic pain, degenrative joint disease
EDS IV
vascular type: think translucent skin, arterial, intestinal, and uterine fragility, arterial ruption, congential hip dislocation
type III collagen disorder
EDX VI
kyphoscoliotic form: scoliosis plus other EDS symptoms
autosomal recessive
lysyl oxidase gene mutaiton
integrin. structure, function
TM proteins with alpha and beta subutnis. ECM proteins bind integrins and proteoglycans bind integrins
how can cells change the ECM?
- traction forces
- deposition of new ECM proteins
- secretion of proteases to degrade the ECM
What are the two types of ECM proteinases?
matrix mattaloproteases that need Ca2+ or Zn2+
serine proteases
in what three ways is ECM remodeling controlled? Include examples
- proteinases secreted in a n inactive form (plasminogen must be activated by tPA)
- bound to cell surface receptors (UPA)
- Protease inhibitors: TMPs (tissue inhibitors of metalloproteases) and serpins
collagen structure
tripple helix made of three polypeptide chains
type IV collagen
found in basement membranes. esp. important in kidney and ear
post-translational modification of collagen
- N-terminus has a signal peptide that designates the collagen for secretion.
- ribosome localized to RER and peptide extruded into RER luman
- signal peptide cleaved to form pro-alpha collagen
- Lys and pro of pro alpha chains are hydroxylated by lysyly hydroxylase and prolyly hydroxylase with the help of ascorbic acid
- glucose or glucose/galactose dimer are attached to some lys residues
- intra and inter molecular disulfide bonds formed btw cys resudies to yield a globular strucuture (protein disulfide isomerase)
- progollagen is secreted from golgi to ECM
- procollagen proteases cleave procollagen to make mature collagen in ECM
- lysyl oxidase helps build lys-lys bridges btw collagens in ECM but requires Cu
lysyl oxidase
enzyme that helps build lys-lys bridges btw collagens in the ECM. requires cu
protein disulfide isomerase
helps with the formation of disulfide bonds btw cys residues at c terminal of alpha chains during the formation of globular collagen
lysyl and prolyl hydroxylase
help hydroxyate the lys and pro resudies of pro alpha chains during collagen synthesis. require ascorbic acid
osteogenesis imperfecta
bone fragility, blue sclera, fractures with minimal trauma, short stature, hearing loss.
most common type of osteogenesis imperfecta
type I. relatively mild
what ype of osteogenesis imperfecta is autosomal recessive?
type III. fractures are usually present at birth and babies have resp problems.
What type of OI usually leads to death in the perinatal period?
type II
