Biomedical Engineering Reference
In-Depth Information
R2
R1 p53R2
R1
R2
p53R2
dNTPs
dNTPs
p53
DNA replication
DNA damage
DNA repair
Figure 6.2
(See companion CD for color igure.) .RNR.catalyzes.a.key.step.in.dNTPs.synthesis.for.DNA.replication.and.
DNA.repair..Mammalian.RNR.subunits,.R1.and.R2.complex,.catalyzes.the.synthesis.of.dNTPs.for.DNA.replica-
tion..After.DNA.damage,.p53-dependent.checkpoint.pathways.induce.p53R2.subunit.by.repressing.R2.
highest.in.S.and.are.absent.in.the.G1/G0.phase.(Liu.et.al..2005)..R2.has.a.short.half-life.(about.
3-4.h).and.is.degraded.when.cells.enter.into.mitosis..This.highly.regulated.R2.degradation.
is. mediated. by. the. anaphase-promoting. complex-cdh1,. whereas. p53R2. lacks. the. cdh1.
recognition.site.to.mediate.this.type.of.regulation.(Chabes.et.al..2003b)..The.constitutive.
low-level.expression.of.p53R2.was.reported.in.all.phases.of.the.cell.cycle.(Hakansson.et.al..
2006)..p53-mutated.cancer.cells.arrest.in.S.and.G2/M.checkpoints.to.repair.damaged.DNA,.
predominately.by.R1.and.R2.subunits..Normal.cells.undergo.p53-mediated.G1.arrest.after.
DNA. damage. and. increase. p53R2. levels. for. DNA. repair. by. degrading. R2. (Lozano. and.
Elledge.2000)..In.contrast.to.the.pronounced.increase.in.dNTP.pools.in.yeast.after.DNA.
damage,.major.increases.in.dNTP.pools.were.not.observed.in.normal.growing.or.resting.
mammalian. cells. after. DNA. damage.. Structural. similarities. between. the. RNR. subunits.
strongly.suggest.that.the.R1.and.R2.subunits.from.all.species.have.overall.similarity.in.the.
three-dimensional.structure.to.the. Escherichia coli ..The.R2.contains.a.heart-shaped.structure.
and.has.the.stable.tyrosyl.radical.and.dinuclear.iron.center..R2.has.375.amino.acids.with.
dimensions.8.×.6.×.5.nm..The.R1.is.the.reductase.component.of.RNR.that.contains.the.active.
and.allosteric.binding.sites.and.has.761.residues..The.R1.dimer.is.S-shaped.with.a.length.of.
10.nm.and.a.width.of.7.5.nm..The.active.site.is.located.in.a.cleft.5.nm.long,.2.nm.deep,.and.
2.nm.wide.between.the.N-terminal.and.α/β.domain.(Eklund.et.al..2001)..This.nano-sized.
cleft.found.in.RNR.is.essential.to.the.DNA.damage.response,.as.inhibition.by.inhibitors.
like.hydroxyurea.can.sensitize.cells.to.DNA-damage-induced.killing.
6.4 The Future for Nanotechnology in DNA Damage
Response and Personalized Medicine
6.4.1  Sensing Damaging Agents with Nanotechnology
Biological.systems.sense.DNA.damage.via.changes.to.the.structure.of.DNA..The.identiication.
and. quantiication. of. DNA. damaging. agents. is. an. exciting. area. of. research. that. uses.
 
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