theory teaching session 1
TRANSCRIPT
8/10/2019 Theory Teaching Session 1
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Genetic Predisposition to Cancer
Dr. Jordi Surrallés, Jan 2015
Topics:
1. Familiar cancer ersus cancer predisposition s!ndromes
2. D"# repair pat$%a!s and $uman disease&. Tar'etin' D"# repair in cancer t$erapeutics. S!nt$etic let$alit!
(. Genetic strate'ies to identi)! cancer suscepti*ilit! 'enes
5. +enc$ to *eadside researc$ in Fanconi anemia
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16 FEBRUARY 2001 VOL 291 SCIENCE
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D"# dama'e response
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D"# dama'e response
From: $ttp:%%%.si'maaldric$.comtec$nical-documentsarticles*io)ilesdna-dama'e-and-repair.$tml
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Cell c!cle durin' D"# dama'e response
From the followin !rti"le#
T$e impact o) a ne'li'ent G2 c$ec/point on 'enomic insta*ilit! and cancer
induction
ar/us *ric$ Penn! #. Je''o
"ature 3eie%s Cancer 4, 61-67 8"oem*er 20049
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From the followin !rti"le#
D"# repair d!sre'ulation )rom cancer drier to t$erapeutic tar'et"icola J. Curtin
"ature 3eie%s Cancer 12, 01-14 8Decem*er 20129
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From the followin !rti"le#
o% nucleotide e;cision repair protects a'ainst cancer
<rrol C. Fried*er'"ature 3eie%s Cancer 1, 22-&&
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Sources o) D"# dama'e and t$eir repair
From the followin !rti"le#
D"# repair d!sre'ulation )rom cancer drier to t$erapeutic tar'et"icola J. Curtin
"ature 3eie%s Cancer 12, 01-14 8Decem*er 20129
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ain D"# lesions and correspondin' D"#-
dama'e-repair pat$%a!s
Postel-=ina!, S. et al. 820129 T$e potential o) e;ploitin' D"#-repair de)ects )or optimi>in' lun' cancer treatment
Nat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2012.&
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Mutations in DNA repair genes
Defective DNA repairGenomic instability
Cell death or Cancer
Somatic level:
sporadic cancer in
the general
population
Germinal level: cancer
predisposition DNA
repair syndromes
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Disease evolution in Fanconi Anemia
Kutler et al., Blood, 2003
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Mutations in DNA repair genes
Defective DNA repairGenomic instability
Cell death or Cancer
Somatic level:
1 mutation
Germinal level:
1 mutation
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+reast cancer ris/ in +3C#2 mutation carriers
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#n'elina Jolie is a +3C# mutation carrier
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Familiar cancer
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D"# repair pat$%a!s
• $ire"t re%!ir-Trans)erases
-P$otol!ases
• $o&'le Str!n( Bre!) *$SB+ re%!ir
-"on-$omolo'ous end ?oinin' 8"<J9
-omolo'ous recom*ination 839
•
-s$ort patc$ +<3
-lon' patc$ +<3
• N&"leoti(e e-"i,ion re%!ir *NER+
-Glo*al 'enome "<3 8GG-"<39-Transcription coupled "<3 8TC-"<39
• .i,m!t"h re%!ir *..R+
•ICL re%!ir *F!n"oni !nemi!/BRCA %!thw!+
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D"# repair pat$%a!s
• $ire"t re%!ir-Trans)erases
-P$otol!ases
• $o&'le Str!n( Bre!) *$SB+ re%!ir
-"on-$omolo'ous end ?oinin' 8"<J9
-omolo'ous recom*ination 839
•
-s$ort patc$ +<3
-lon' patc$ +<3
• N&"leoti(e e-"i,ion re%!ir *NER+
-Glo*al 'enome "<3 8GG-"<39-Transcription coupled "<3 8TC-"<39
• .i,m!t"h re%!ir *..R+
•ICL re%!ir *F!n"oni !nemi!/BRCA %!thw!+
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@6-alAuil G 8#:T9
@(-alAuil T 8C:G9
-me 'uan na me rans erasa -
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D"# repair pat$%a!s
• $ire"t re%!ir-Trans)erases
-P$otol!ases
• $o&'le Str!n( Bre!) *$SB+ re%!ir
-"<J
-3
•
-s$ort patc$ +<3
-lon' patc$ +<3
• N&"leoti(e e-"i,ion re%!ir *NER+
-Glo*al 'enome "<3 8GG-"<39-Transcription coupled "<3 8TC-"<39
• .i,m!t"h re%!ir *..R+
• ICL re%!ir *F!n"oni !nemi!/BRCA %!thw!+
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DS+ repair *! "<J and $omolo'ous recom*ination
From the followin !rti"le#
C$romatin d!namics and t$e preseration o) 'enetic in)ormationJessica #. Do%ns, ic$el C. "ussen>%ei' #ndré "ussen>%ei'
"ature ((4, 751-75821 June 20049
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DS+ repair *! "<J and $omolo'ous recom*ination
From the followin !rti"le#
C$arit! *e'ins at $ome: non-codin' 3"# )unctions in D"# repair
Dipan?an C$o%d$ur!, Boun' <un C$oi arie <e +rault
"ature 3eie%s olecular Cell +iolo'! 1(, 11-17 8arc$ 201&9
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33:
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"<J:
$ttp:%%%.!outu*e.com%atc$?@rm-sH-B?'
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@ri'in o) D"# dou*le strand *rea/s 8DS+9
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Ataxia telangiectasia (ATM)
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Nijmegen breakage syndrome (NBS1)
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+loom s!ndrome 8+9
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Seckle syndrome (ATR)
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"<J can *e error prone
From: $ttp:%%%.si'maaldric$.comtec$nical-documentsarticles*io)ilesdna-dama'e-and-repair.$tml
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Gene editin' %it$ en'ineered nucleases is
*ased on DS+ repair 8T#<", C3ISP39
From: $ttp:%%%.tool'en.com$tml/ortec$nolo'!'enEen'Enuc.p$p
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D"# repair pat$%a!s
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D"# repair pat$%a!s
• $ire"t re%!ir-Trans)erases
-P$otol!ases
• $o&'le Str!n( Bre!) *$SB+ re%!ir
-"on-$omolo'ous end ?oinin' 8"<J9
-omolo'ous recom*ination 839
•
-s$ort patc$ +<3
-lon' patc$ +<3
• N&"leoti(e e-"i,ion re%!ir *NER+
-Glo*al 'enome "<3 8GG-"<39-Transcription coupled "<3 8TC-"<39
• .i,m!t"h re%!ir *..R+
• ICL re%!ir *F!n"oni !nemi!/BRCA %!thw!+
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+ase e;cision repair 8+<39
Glicosilasa:
corte enlace 'licoslico
entre la *ase ! la ri*osa
de?a un sitio #P
#P endonucleasa:
e;tremo 5K del sitio #P
D"# polL:
rellena el $ueco
elimina el 'rupo ri*osa-)os)ato8actiidad liasa9
Comple?o M3CC1-li'asaIII:
sellado de la mella
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+<3: t%o pat$%a!s
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+<3: t%o pat$%a!s
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+<3 8SP9
$ttp:%%%.!outu*e.com%atc$42oT6"70ic
+<3 8P9
$ttp:%%%.!outu*e.com%atc$'(/$3@a@@6clist
PF&FF#<#+D7C1(0
D"# repair pat$%a!s
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D"# repair pat$%a!s
•$ire"t re%!ir
-Trans)erases
-P$otol!ases
• $o&'le Str!n( Bre!) *$SB+ re%!ir
-"on-$omolo'ous end ?oinin' 8"<J9
-omolo'ous recom*ination 839
•
-s$ort patc$ +<3-lon' patc$ +<3
• N&"leoti(e e-"i,ion re%!ir *NER+
-Glo*al 'enome "<3 8GG-"<39-Transcription coupled "<3 8TC-"<39
• .i,m!t"h re%!ir *..R+
• ICL re%!ir *F!n"oni !nemi!/BRCA %!thw!+
Nucleotide excision repair (NER)
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Nucleotide excision repair (NER)
recognition
dual incision
UV
excision
DNA synthesis
ligation
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Initial Steps of Transcription-Coupled NEREarly Stages of Global GenomeRepair
Fi l St f E k ti NER
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Final Steps of Eukaryotic NER
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"<3 8GG9
$ttp:%%%.!outu*e.com%atc$*'7")@2N
"<3 and $uman disease
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From the followin !rti"le#
D"# repair de)icienc! and neurolo'ical diseasePeter J. cHinnon
"ature 3eie%s "euroscience 10, 100-112 8Fe*ruar! 20079
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Xeroderma pigmentosum
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Cockayne syndrome
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"<3
GG3 TC3
Cockayne syndromeXeroderma pigmentosum
Skin cancer No cancer!
D"# repair pat$%a!s
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• $ire"t re%!ir
-Trans)erases
-P$otol!ases
• $o&'le Str!n( Bre!) *$SB+ re%!ir
-"on-$omolo'ous end ?oinin' 8"<J9
-omolo'ous recom*ination 839
•
-s$ort patc$ +<3-lon' patc$ +<3
• N&"leoti(e e-"i,ion re%!ir *NER+
-Glo*al 'enome "<3 8GG-"<39-Transcription coupled "<3 8TC-"<39
• .i,m!t"h re%!ir *..R+
• ICL re%!ir *F!n"oni !nemi!/BRCA %!thw!+
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D"# pol $ae proo)-readin' actiit!
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D"# pol $ae proo) readin' actiit!
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he E,"heri"hi! "oli .ethl$ire"te(
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.i,m!t"h Re%!ir Re!"tion
T$e oerall repair reaction can *e diided into seeral
steps:
• mismatc$-de endent incision o) t$e unmet$ lated
strand at a $emi-met$!lated G#TC site.
• <;cision o) t$at portion o) t$e incised strand spannin't$e sin'le-strand *rea/ and t$e mispair.
• 3epair o) t$e ensuin' 'ap *! D"# s!nt$esis and
li'ation.
uman mismatc$ repair 839 pat$%a!
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From the followin !rti"le#
#ID and mismatc$ repair in anti*od! diersi)ication
#l*erto artin att$e% D. Sc$ar)) "ature 3eie%s Immunolo'! 2, 605-61( 8#u'ust 20029
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3
$ttp:%%%.!outu*e.com%atc$BS6<HnNc0
$ttp:%%%.!outu*e.com%atc$d'P$1Ai'4s
icrosatellite insta*ilit!
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!
Distinct molecular pat$%a!s )or t$e deelopment o)
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de)ectie D"# 3 and SI- in colon cancer
Sinicrope, F. #. 820109 D"# mismatc$ repair and ad?uant c$emot$erap! in sporadic colon cancer
Nat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2007.2&5
D"# repair pat$%a!s
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• $ire"t re%!ir
-Trans)erases
-P$otol!ases
• $o&'le Str!n( Bre!) *$SB+ re%!ir
-"on-$omolo'ous end ?oinin' 8"<J9
-omolo'ous recom*ination 839
•
-s$ort patc$ +<3-lon' patc$ +<3
• N&"leoti(e e-"i,ion re%!ir *NER+
-Glo*al 'enome "<3 8GG-"<39
-Transcription coupled "<3 8TC-"<39
• .i,m!t"h re%!ir *..R+
• ICL re%!ir *F!n"oni !nemi!/BRCA %!thw!+
Interstrand crosslink repair (ICLR)
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Fork stalling
Unhooking
Translesion sythesis
Recombination
Fanconi anemia
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FA-A FA-C
D"# repair as a t$erapeutic tar'et
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Postel-=ina!, S. et al. 820129 T$e potential o) e;ploitin' D"#-repair de)ects )or optimi>in' lun' cancer treatment
Nat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2012.&
D"# repair pat$%a!s inoled in repairin' to;ic D"#
lesions )ormed *! cancer treatments
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elleda! et al. "ature 3eie%s Cancer , 17&-20( 8arc$ 2009
S!nt$etic let$alit! in cancer treatment
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From the followin !rti"le#
D"# repair d!sre'ulation )rom cancer drier to t$erapeutic tar'et
"icola J. Curtin
"ature 3eie%s Cancer 12, 01-14 8Decem*er 20129
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D"#-repair *iomar/ers and t$erapeutic implication
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Postel-=ina!, S. et al. 820129 T$e potential o) e;ploitin' D"#-repair de)ects )or optimi>in' lun' cancer treatmentNat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2012.&
"<3 in cancer and as tar'et in cancer treatment
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From the followin !rti"le#
D"# repair d!sre'ulation )rom cancer drier to t$erapeutic tar'et
"icola J. Curtin
"ature 3eie%s Cancer 12, 01-14 8Decem*er 20129
+<3 in cancer and as tar'et in cancer treatment
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From the followin !rti"le#
"icola J. Curtin
"ature 3eie%s Cancer 12, 01-14 8Decem*er 20129
3 in cancer and as tar'et in cancer treatment
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From the followin !rti"le#
D"# repair d!sre'ulation )rom cancer drier to t$erapeutic tar'et
"icola J. Curtin
"ature 3eie%s Cancer 12, 01-14 8Decem*er 20129
3 in cancer and as tar'et in cancer treatment
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From the followin !rti"le#
D"# repair d!sre'ulation )rom cancer drier to t$erapeutic tar'et
"icola J. Curtin
"ature 3eie%s Cancer 12, 01-14 8Decem*er 20129
DS+ repair in cancer and as tar'et in cancer treatment
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From the followin !rti"le#
D"# repair d!sre'ulation )rom cancer drier to t$erapeutic tar'et
"icola J. Curtin
"ature 3eie%s Cancer 12, 01-14 8Decem*er 20129
S!nt$etic let$alit! in tumors )rom BRCA1 and BRCA2
mutation carriers treated %it$ P#3P in$i*itors
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Nature Medicine 17, 283–284 (2011)
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Nature Biotechnology 29,373–374(2011)
ec$anism o) s!nt$etic let$alit! *et%een BRCA
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de)icienc! and P#3P in$i*ition
+aner?ee, S.et al.
820109 a/in' t$e *est o) P#3P in$i*itors in oarian cancerNat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2010.116
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<))ects o) P#3P in$i*ition on BRCA2-mutant cells
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+aner?ee, S. et al. 820109 a/in' t$e *est o) P#3P in$i*itors in oarian cancer
Nat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2010.116
3AR3 inhi'itor 4 3AR3 inhi'itor
CT scans o) t%o patients %it$ adanced oarian
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cancer a)ter P#3Pi t$erap!
+aner?ee, S. et al. 820109 a/in' t$e *est o) P#3P in$i*itors in oarian cancer
Nat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2010.116
<;amples o) DD3 in$i*itors in clinical use or in deelopment
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Nature 481, 287–294 (19 January 2012)
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<;periments to *e done:
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• = sensitiit! o) MP de)icient s/in cells
•#*normal repair /inetics o) =-li'$t inducedD"# dama'e in MP de)icient s/in cells
•
tumor cells de)icient in t$e F# pat$%a! on ICrepair
• P#3P in$i*ition )or selectie /illin' o) +3C#1
de)icient tumor cells• omolo'ous recom*ination repair o) DS+
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60%
90%
i n i n g 6 - 4 P P
f o c i
60%
90%
i n i n g 6 - 4 P P
f o c i
4 8 12 16 20 2400
30%
% o
f c e l l s c
o n t a
Time (h) after UV irradiation
4 8 12 16 20 2400
30%
% o
f c e l l s c
o n t a
Time (h) after UV irradiation
<;periments to *e done:
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• = sensitiit! o) MP de)icient s/in cells
• #*normal repair /inetics o) =-li'$t inducedD"# dama'e in MP de)icient s/in cells
•
tumor cells de)icient in t$e F# pat$%a! on ICrepair
• P#3P in$i*ition )or selectie /illin' o) +3C#1
de)icient tumor cells• omolo'ous recom*ination repair o) DS+
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51# 78:
524.# 1;80:
51# 08:
524.# 218: < e ! l t
h 0 $ o n o r
..C 4 ..C
51# =682:
524.# ;687:
51# 086:
524.# 1189:
51# =8:
524.# 1087:
51# 668:
524.# 298;:
F A 2 A 3
! t i e n t
4 FANCA 4 FANCA
<;periments to *e done:
8/10/2019 Theory Teaching Session 1
http://slidepdf.com/reader/full/theory-teaching-session-1 96/99
• = sensitiit! o) MP de)icient s/in cells
• #*normal repair /inetics o) =-li'$t inducedD"# dama'e in MP de)icient s/in cells
•
tumor cells de)icient in t$e F# pat$%a! on ICrepair
• P#3P in$i*ition )or selectie /illin' o) +3C#1
de)icient tumor cells• omolo'ous recom*ination repair o) DS+
8/10/2019 Theory Teaching Session 1
http://slidepdf.com/reader/full/theory-teaching-session-1 97/99
<;periments to *e done:
8/10/2019 Theory Teaching Session 1
http://slidepdf.com/reader/full/theory-teaching-session-1 98/99
• = sensitiit! o) MP de)icient s/in cells
• #*normal repair /inetics o) =-li'$t inducedD"# dama'e in MP de)icient s/in cells
•
tumor cells de)icient in t$e F# pat$%a! on ICrepair
• P#3P in$i*ition )or selectie /illin' o) +3C#1
de)icient tumor cells• omolo'ous recom*ination repair o) DS+
<R re%!ir !,,!<R %rofi"ien" &,in $R5F3 ,,tem#