Inhibition of DNA damage repair by artificial activation of PARP with siDNA

摘要: One of the major early steps repair is recruitment proteins at damage site, and this coordinated by a cascade modifications controlled 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 Pbait) to promote DNA-dependent protein kinase (DNA-PK) PARP activation. Dbait bound induced both DNA-PK activities, whereas Pbait acts only on PARP. Therefore, comparative study two allows analysis respective roles signaling pathways: recruit involved in break (PARP, XRCC1 PCNA) prevent their chromosomal damage. Dbait, but not Pbait, also inhibits (53BP1, NBS1, RAD51 DNA-PK). By these ways, disorganize repair, thereby sensitizing cells various treatments. Single-strand inhibition depends direct trapping main molecules. Double-strand may be indirect, resulting from phosphorylation chromatin targets activated DNA-PK. The confirmed synthetic lethality with BRCA mutations.