000129872 001__ 129872
000129872 005__ 20190316234436.0
000129872 0247_ $$2doi$$a10.1128/JVI.00358-08
000129872 02470 $$2ISI$$a000257770500013
000129872 037__ $$aARTICLE
000129872 245__ $$aRecombinant Adeno-Associated viral vectors are deficient in provoking a DNA damage response
000129872 269__ $$a2008
000129872 260__ $$c2008
000129872 336__ $$aJournal Articles
000129872 520__ $$aAdeno-associated virus type 2 (AAV2) provokes a DNA damage response that mimics a stalled replication fork. We have previously shown that this response is dependent on ataxia telangiectasia-mutated and Rad3- related kinase and involves recruitment of DNA repair proteins into foci associated with AAV2 DNA. Here, we investigated whether recombinant AAV2 (rAAV2) vectors are able to produce a similar response. Surprisingly, the results show that both single-stranded and double-stranded green fluorescent protein-expressing rAAV2 vectors are defective in producing such a response. We show that the DNA damage signaling initiated by AAV2 was not due to the virus-encoded Rep or viral capsid proteins. UV-inactivated AAV2 induced a response similar to that of untreated AAV2. This type of DNA damage response was not provoked by other DNA molecules, such as single-stranded bacteriophage M13 or plasmid DNAs. Rather, the results indicate that the ability of AAV2 to produce a DNA damage response can be attributed to the presence of cis-acting AAV2 DNA sequences, which are absent in rAAV2 vectors and could function as origins of replication creating stalled replication complexes. This hypothesis was tested by using a single-stranded rAAV2 vector containing the p5 AAV2 sequence that has previously been shown to enhance AAV2 replication. This vector was indeed able to trigger DNA damage signaling. These findings support the conclusion that efficient formation of AAV2 replication complexes is required for this AAV2-induced DNA damage response and provide an explanation for the poor response in rAAV2-infected cells.
000129872 700__ $$aFragkos, Michalis
000129872 700__ $$aBreuleux, Madlaina
000129872 700__ $$aClement, Nathalie
000129872 700__ $$g169405$$aBeard, Peter$$0243602
000129872 773__ $$j82$$tJOURNAL OF VIROLOGY$$k15$$q7379-7387
000129872 8564_ $$uhttps://infoscience.epfl.ch/record/129872/files/JV08.pdf$$zn/a$$s714746
000129872 909C0 $$xU11778$$0252243$$pGR-BEARD
000129872 909CO $$ooai:infoscience.tind.io:129872$$qGLOBAL_SET$$pSV$$particle
000129872 937__ $$aGR-BEARD-ARTICLE-2008-001
000129872 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000129872 980__ $$aARTICLE