Biomedical Engineering Reference
In-Depth Information
model. (Matthews. et. al.. 2007).. Moreover,. a. synthetic. lethality. between. a. PARP. inhibitor.
and.BRCA1/BRCA2-deicient.cells.shows.encouraging.results.for.the.application.of.a.DNA.
repair.inhibitor..Synthetic.lethal.describes.a.genetic.interaction.where.the.combination.of.
mutations.or.inactivation.in.two.or.more.genes.leads.to.cell.death,.whereas.a.mutation.in.
only.one.of.these.genes.does.not..In.normal.cells,.inhibition.of.PARP.activity.accumulates.
and. arrests. DNA. replication. forks. at. the. damage. site,. leading. to. double-strand. breaks,.
which.are.repaired.by.homologous.recombination.in.replicating.cells..However,.the.cells.
with.deicient.homologous.recombination,.such.as.breast.or.ovarian.cancers.with.BRCA1/
BRCA2. deiciency,. are. unable. to. process. the. DNA. repair. caused. by. a. PARP. inhibitor.
(Bryant.et.al..2005,.Farmer.et.al..2005)..Synthetic.lethality.is.a.new.therapeutic.concept.to.
minimize.the.toxicity.in.normal.cells.upon.exposure.to.DNA.damage.or.repair.inhibitors..
The.number.of.genes.involved.in.DNA.repair.or.in.the.cell-cycle.checkpoint.is.deicient.
or.mutated.in.various.types.of.cancers..For.example,.there.are.deiciencies.in.BRCA1.and.
BRCA2.in.breast.and.ovarian.cancer;.ATM,.Nbs1,.and.Lig4.in.leukemia;.Mre11.and.CtIP.
in.colon.cancer;.and.Rad.51B.in.lymphoma.and.uterine.leiomyoma.(Helleday.2010)..It.is.
important.to.discover.new.synthetic.lethality.relationships.for.targeting.cancer.cells.with.
a.deiciency.in.DNA.damage.response.molecules.
DNA. mutations. that. disrupt. the. function. of. key. DDR. genes. can. result. in. the.
accumulation.of.mutations.and.widespread.genomic.instability,.which.in.turn.contributes.
to. disease. pathologies. like. cancer.. Indeed,. inherited. defects. in. components. of. the. DDR.
pathway,.such.as.ATM,.BRCA1,.and.p53,.are.known.to.cause.hypersensitivity.to.ionizing.
radiation.(radiosensitivity).and.a.predisposition.to.cancer.development.(Lavin.and.Shiloh.
1997,.Malkin.et.al..1990,.Miki.et.al..1994)..It.is.becoming.increasingly.clear.that.individuals.
with. gene. polymorphisms. or. mutations. require. personalized. healthcare. strategies. that.
consider.their.underlying.genome.sequence..Whole.genome.sequencing.for.personalized.
medicine.is.not.a.new.concept;.however,.recent.advances.in.nanoscale.sequencing.using.
a.semiconductor.platform.promises.to.markedly.reduce.the.cost.and.time.associated.with.
sequencing.large.amounts.of.DNA.and.speciically.DNA.damage.response.genes.
Rothberg. et. al.. (2011). took. this. approach. to. DNA. sequencing. on. the. nanoscale. using.
integrated.circuits.that.function.as.ion-sensitive.ield-effect.transistors.(ISFETs),.allowing.
them. to. take. advantage. of. the. scalability. and. low-costs. associated. with. semiconductor.
manufacturing.. Essentially,. ISFETs. that. contain. a. metal-oxide-sensing. layer. contact.
individual.wells.in.which.the.DNA.polymerase-dependent.sequencing.reaction.releases.
H
+
. during. dNTP. incorporation. into. the. growing. strand. of. template. DNA. (Rothberg.
et. al.. 2011).. As. each. dNTP. is. lowed. separately. into. the. reaction. well,. the. change. in. pH.
indicates.complimentary.base.pairing.and.successful.addition.to.the.unknown.template,.
producing. direct. sequence. information.. The. resulting. DNA. sequencing. technology. has.
implications. as. a. personalized. genome. sequencer,. with. p53,. BRCA1,. BRCA2,. ATM,. and.
MRN. components. important. targets,. with. resulting. information. poised. to. increase. the.
eficacy.of.DNA.damage-based.chemotherapeutics.
6.5 Conclusions and Perspectives
Overall,.nano-based.strategies.connected.to.the.DDR.are.poised.to.play.a.pivotal.role.in.
nanomedicine:.SWCNT.that.detect.luctuations.of.intracellular.ROS.and.integrated.circuits.
that.function.as.nanoscale.DNA.sequencers..All.have.the.potential.to.greatly.enhance.our.
