Inhibition of DNA damage repair by artificial activation of PARP with siDNA.
Nucleic Acids Research. 2013-06-12; 41(15): 7344-7355
DOI: 10.1093/nar/gkt522
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1. Nucleic Acids Res. 2013 Aug;41(15):7344-55. doi: 10.1093/nar/gkt522. Epub 2013
Jun 12.
Inhibition of DNA damage repair by artificial activation of PARP with siDNA.
Croset A(1), Cordelières FP, Berthault N, Buhler C, Sun JS, Quanz M, Dutreix M.
Author information:
(1)Institut Curie, CNRS-UMR3347, INSERM-U1021, 91405 Orsay, France, DNA
Therapeutics, Génopole, 91000 Evry, France, Institut Curie, CNRS-UMR3348,
Plateforme PICT-IBiSA, 91405 Orsay, France and Museum National d’Histoire
Naturelle, USM503, 75231 Paris, France.
One of the major early steps of repair is the recruitment of repair proteins at
the damage site, and this is coordinated by a cascade of modifications controlled
by phosphatidylinositol 3-kinase-related kinases and/or poly (ADP-ribose)
polymerase (PARP). We used short interfering DNA molecules mimicking
double-strand breaks (called Dbait) or single-strand breaks (called Pbait) to
promote DNA-dependent protein kinase (DNA-PK) and PARP activation. Dbait bound
and induced both PARP and DNA-PK activities, whereas Pbait acts only on PARP.
Therefore, comparative study of the two molecules allows analysis of the
respective roles of the two signaling pathways: both recruit proteins involved in
single-strand break repair (PARP, XRCC1 and PCNA) and prevent their recruitment
at chromosomal damage. Dbait, but not Pbait, also inhibits recruitment of
proteins involved in double-strand break repair (53BP1, NBS1, RAD51 and DNA-PK).
By these ways, Pbait and Dbait disorganize DNA repair, thereby sensitizing cells
to various treatments. Single-strand breaks repair inhibition depends on direct
trapping of the main proteins on both molecules. Double-strand breaks repair
inhibition may be indirect, resulting from the phosphorylation of double-strand
breaks repair proteins and chromatin targets by activated DNA-PK. The DNA repair
inhibition by both molecules is confirmed by their synthetic lethality with BRCA
mutations.
DOI: 10.1093/nar/gkt522
PMCID: PMC3753643
PMID: 23761435 [Indexed for MEDLINE]