Biomedical Engineering Reference
In-Depth Information
If. left. unrepaired,. DNA. lesions. can. cause. genomic. instability. that. can. lead. to. undesir-
able.mutations,.loss.of.genetic.information,.and.either.cellular.death.or.transformation.to.
a.cancerous.cell.in.a.multicellular.organism.(van.den.Bosch.et.al..2003,.Branzei.and.Foiani.
2008,. Michel. et. al.. 1997,. Sun. et. al.. 1989).. Fortunately,. eukaryotes. have. multiple. enzymes.
and.mechanisms.to.promote.the.repair.of.DNA.damage..Enzymes.associated.with.the.cel-
lular.DNA.damage.response.must.identify.lesions.in.a.huge.excess.of.normal.DNA.that,.in.
humans,.is.akin.to.inding.one.needle.in.a.haystack.consisting.of.3.billion.straws..Scientists.
working. with. DNA. and. associated. damage. have. been. using. structural. and. molecular.
approaches.to.study.sub-100.nm.regions.for.over.50.years..Nucleic.acid.scientists.were.argu-
ably.some.of.the.earliest.nanotechnologists,.with.x-ray.crystallography,.NMR,.and.electron.
microscopy.proving.to.be.techniques.that.have.provided.insight.into.the.biology.of.DNA.
and.DNA.repair..These.structural.techniques.have.highlighted.the.many.interfaces.and.sub-
100.nm.features.(i.e.,.nano-features).important.for.understanding.the.enzymes.and.cellular.
strategies.used.to.maintain.the.coding.integrity.of.DNA..Most.DNA.damage.at.the.single-.or.
double-strand.level.falls.into.the.category.of.damage.at.the.nanoscale,.with.enzymes.associ-
ated.with.single-strand.and.double-strand.break.repair.mechanism.eficiently.recognizing.
these.nano-features..Repair.of.DNA.breaks.thus.requires.precision.on.the.nanometer.scale.
Molecular.and.structural.studies.of.DNA.and.the.associated.enzymes.that.maintain.DNA.
integrity.have.highlighted.the.use.of.nano-features.inherent.to.DNA.and.associated.with.
response. systems. for. damage. identiication. and. activation. of. DNA. repair. pathways.. In.
addition,.a.number.of.old.(structure.based).and.new.(quantum.dots).nanotechnology-based.
approaches.have.been.used.to.better.understand.the.mechanism.of.action.associated.with.
the.DNA.damage.response.(Friedberg.et.al..2005,.Kad.et.al..2010)..Understanding.the.mech-
anism.of.action.related.to.the.DNA.damage.response.has.been.particularly.important.from.
a. human. health. perspective,. as. these. associated. pathways. act. as. redundant. systems. that.
have. confounded. some. chemotherapeutic. regiments.. As. DNA. damage. is. one. way. to. kill.
rapidly.dividing.cancer.cells,.a.detailed.understanding.of.working.DNA.repair.systems.in.
cancer.cells.is.useful.for.designing.treatment.regiments..New..nanotechnology-based.dam-
age.detection.and.sequencing.approaches,.falling.under.the.auspices.of.personalized.medi-
cine,.are.predicted.to.further.our.understanding.of.the.DNA.damage.response.in.human.
diseases.and.should.lead.to.advances.in.cancer.management..Our.chapter.review.highlights.
the.molecular.mechanisms.that.utilize.enzyme.and.DNA-based.nano-features.to.safeguard.
the.integrity.of.one.of.the.cells'.most.abundant.nanomaterials,.DNA,.as.well.as.nanotechnol-
ogy.approaches.that.are.predicted.to.be.important.for.disease.diagnosis.and.therapy.
6.1.1
Nano-Features Associated with Biological Sensing
of DNA Damage and the initial response
In. response. to. DNA. lesions,. cells. activate. DNA. damage. response. pathways. to. protect.
genome.integrity.and.to.promote.the.survival.of.the.cell.or.organism..The.DNA.damage.
response.is.a.network.of.interacting.signal-transduction.pathways.that.consists.of.sensor,.
transducer,. and. effecter. molecules.. In. humans,. there. are. over. 100. known. DNA. repair.
proteins. participating. in. direct-,. base. excision-,. nucleotide. excision-,. mismatch-,. single-
strand-,. and. double-strand. break. repair. (Friedberg. et. al.. 2005,. Wood. et. al.. 2001,. 2005)..
Depending.on.the.type.of.DNA.damage.and.the.phase.of.cell.cycle,.several.independent.
molecular. complexes. sense. and. signal. different. types. of. DNA. damage. (Branzei. and.
Foiani. 2008).. For. the. purpose. of. this. review,. we. will. concentrate. on. strand. breaks,. with.
a.clean.double-strand.break.providing.a.2.4.nm.diameter.dimension,.as.well.as.increased.
nucleotide.access.and.single-stranded.character.for.sensing.purposes.
