null
US
Sign In
Sign Up for Free
Sign Up
We have detected that Javascript is not enabled in your browser. The dynamic nature of our site means that Javascript must be enabled to function properly. Please read our
terms and conditions
for more information.
Next up
Copy and Edit
You need to log in to complete this action!
Register for Free
108586
Recognition and repair of deaminated pyrimidines
Description
Protein Form and Function (Protein nucleic acids) Mind Map on Recognition and repair of deaminated pyrimidines, created by sophie_connor on 25/05/2013.
No tags specified
protein form and function
protein nucleic acids
protein form and function
protein nucleic acids
Mind Map by
sophie_connor
, updated more than 1 year ago
More
Less
Created by
sophie_connor
over 11 years ago
70
0
0
Resource summary
Recognition and repair of deaminated pyrimidines
Cytosine deamination
Water can attack the 4 position and release ammonia
Changes cysteine to uracil
Not a normal component of DNA
Changes base pairing properties
Uracil would rather bind adenine not guanine
Mutation occurs
Consequences
GU mismatch base repair occurs
DNA polymerases moving along the DNA strand during synthesis only care if the nucleotides are bound to those in template strands
During replication, one strand ends up correctly base paired (GC)
Other stand ends up incorrectly base paired (AU)
Another round of replication results in the insertion of a thymine (AT)
Fixed mutation
If this keeps recurring then cytosine levels will be reduced
Progressive loss of GC in DNA
Uracil repair
Base excision repair
A cycle of replication has already occurred and adenine has been inserted
Uracil-DNA glycsoylase (monofunctional) recognises uracil
Uracil is cut by the N-glycosidic bond leaving an abasic site
AP endonuclease cuts out the sugar leaving a gap in the DNA
Leaves a 3' hydroxyl and 5'dRP
End processing enzyme such as PNKP has a kinase domain which phosphorylates 5' ends and a phosphatase domain which removes phosphate from 3' end
Must be 5' phosphate and 3' hydroxyl for DNA polymerase to work
Gap is repaired by short patch repair
DNA polymerase beta fills the gap with the correct base
DNA ligase III and XRCC1 joins the gap
Uracil DNA glycosylase
Specific to uracil
Uracil binds into pocket by hydrogen bonds
Thymine can't fit in pocket as it is sterically hindered
5' position of thymine is packed against the ring
Single strand breaks are dangerous because if a replication fork were to move through the DNA and it is not anchored it would kill the cell
Can be reversed by cytosine reamination
Corrects pro-mutagenic G:U formed by deamination
Converts A:U base pairs into mutagenic A:C mispairs
Thymine
Why?
Thymine bound to adenine is more stable than cytosine
Cytosine's instability renders uracil unreliable as the base pairing partner of adenine in DNA
In DNA, intentional uracil is flagged to alert the DNA it should be there and is not removed
How?
Thymine is made the folic acid cycle
At the bottom of the cycle there is a mixture of thymine and uracil incorporated into the DNA
dUTPase is an enzyme only uracil can bind to
Destroys dUTP and dephosphorylates it
Minimises dUTP incorporation into DNA
Cancer drugs and thymine in the folic acid cycle
Tomudex
Destroys thymine chain and leaves uracil
No TTP to compete with uracil and the cell starts to incorporate lots of uracil into the DNA
dUTPase cuts uracil out the DNA
Lots of single strand breaks form
The cell cannot divide and replicate due to lots of SSBs
Methotrexate
Blocks folic acid cycle directly and starves the cell of methyl units
Not enough thymine to make DNA and eventually the cells die
Effective at killing rapidly replicating cells
dUTP/dTTP subversion
PBS2 is a bacteriophage that affects bacilli
Has a thymine
Lots of restriction enzymes don't work as they are not expecting a thymine
Has resistance to innate immune system
Too much uracil is inserted into DNA and then removed resulting in lots of SSBs
dTMPase converts dMTP to dT which does nothing
dUMP cycle needs to be deactivated to prevent DNA degradation
dCTP deaminase is introduced
Takes cytosine into DNA and removes amino group
Enough UTP is made that dUTPase is inhibited
Uracil DNA glycosylase inhibitor
Sits where DNA sits and replicates interaction that the DNA makes with the enzyme
Stops uracil containing DNA from being degraded
Thymine DNA glycosylase
Removes thymine when mismatched with guanine
Cytosine methylation
Addition of methyl group makes it more likely the amine group will be lost
If it recognises thymine bound with adenine it will shred the DNA unnecessarily
Structure and function in the uracil-DNA glycosylase superfamily
Deamination of cytosine to uracil is a major pro-mutagenic event
Repair by base excision repair pathway
Family 1 enzymes
Active against uracil in ssDNA and dsDNA
Recognise uracil explicitly in an extrahelical conformation via combination of protein and bound-water interactions
Extrahelical recognition requires efficient process of substrate location by base sampling by hopping or gliding along DNA
Specific for uracil in DNA
Well understood in HSV1
Shape of pocket provides selection against adenine or guanine
Entry of pyrimidines such as thymine is blocked due to a side chain of a tyrosine residue
Selection of bases able to enter is mediated by hydrogen bonds in pocket
Amide side chain of conserved asparagine thought to differentiate between cytosine and uracil
Asparagine head group makes parallel hydrogen bond interactions with uracil ring
Orientation of head group is critical for selection of uracil over cytosine
Family 2 enzymes
Mismatch specifc
Recognise widowed guanine on complementary strand
Broader specificity
Excise uracil from mismatches with guanine
Only active for GU mispairs
Deep pocket provides specificity for uracil
Highly conserved catalytic aspartate and histidine
MUG
Family 3 and 4 enzymes have similar folds and common active site motifs
Family 3
Excise uracil from ssDNA and dsDNA in both GU and AU mispairs
No activity against GT mismatches
Prefers ssDNA
Resembles MUG but has aspartate and glycine rather than tyrosine
SMUG
Family 4
Glycine in final position instead of tyrosine like family 1
Show full summary
Hide full summary
Want to create your own
Mind Maps
for
free
with GoConqr?
Learn more
.
Similar
Repair of DNA double strand breaks by protein repair machines
sophie_connor
Protein folding
sophie_connor
Other structural methods
sophie_connor
Nuclear Magnetic Resonance
sophie_connor
Protein misfolding
Jen Harris
Protein evolution
sophie_connor
DSB repair by protein machines
sophie_connor
Protein misfolding
sophie_connor
Double strand break repair by protein repair machines
sophie_connor
Introduction
Jen Harris
Protein Evolution
Jen Harris
Browse Library