Universität zu Köln

Millet, Rachel, Jolinon, Nelly, Berger, Gregory, Cimarelli, Andrea, Greco, Anna, Bertrand, Pascale, Odenthal, Margarete, Buening, Hildegard and Salvetti, Anna ORCID: 0000-0003-2007-8350 (2015). Impact of the MRN Complex on Adeno-Associated Virus Integration and Replication during Coinfection with Herpes Simplex Virus 1. J. Virol., 89 (13). S. 6824 - 6835. WASHINGTON: AMER SOC MICROBIOLOGY. ISSN 1098-5514

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Abstract

Adeno-associated virus (AAV) is a helper-dependent parvovirus that requires coinfection with adenovirus (AdV) or herpes simplex virus 1 (HSV-1) to replicate. In the absence of the helper virus, AAV can persist in an episomal or integrated form. Previous studies have analyzed the DNA damage response (DDR) induced upon AAV replication to understand how it controls AAV replication. In particular, it was shown that the Mre11-Rad50-Nbs1 (MRN) complex, a major player of the DDR induced by doublestranded DNA breaks and stalled replication forks, could negatively regulate AdV and AAV replication during coinfection. In contrast, MRN favors HSV-1 replication and is recruited to AAV replication compartments that are induced in the presence of HSV-1. In this study, we examined the role of MRN during AAV replication induced by HSV-1. Our results indicated that knockdown of MRN significantly reduced AAV DNA replication after coinfection with wild-type (wt) HSV-1 or HSV-1 with the polymerase deleted. This effect was specific to wt AAV, since it did not occur with recombinant AAV vectors. Positive regulation of AAV replication by MRN was dependent on its DNA tethering activity but did not require its nuclease activities. Importantly, knockdown of MRN also negatively regulated AAV integration within the human AAVS1 site, both in the presence and in the absence of HSV-1. Altogether, this work identifies a new function of MRN during integration of the AAV genome and demonstrates that this DNA repair complex positively regulates AAV replication in the presence of HSV-1. IMPORTANCE Viral DNA genomes trigger a DNA damage response (DDR), which can be either detrimental or beneficial for virus replication. Adeno-associated virus (AAV) is a defective parvovirus that requires the help of an unrelated virus such as adenovirus (AdV) or herpes simplex virus 1 (HSV-1) for productive replication. Previous studies have demonstrated that the cellular Mre11-Rad50Nbs1 (MRN) complex, a sensor and regulator of the DDR, negatively regulates AAV replication during coinfection with AdV, which counteracts this effect by inactivating the complex. Here, we demonstrate that MRN positively regulates AAV replication during coinfection with HSV-1. Importantly, our study also indicates that MRN also favors integration of AAV genomes within the human AAVS1 site. Altogether, this work indicates that MRN differentially regulates AAV replication depending on the helper virus which is present and identifies a new function of this DNA repair complex during AAV integration.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Millet, Rachel UNSPECIFIED UNSPECIFIED UNSPECIFIED Jolinon, Nelly UNSPECIFIED UNSPECIFIED UNSPECIFIED Berger, Gregory UNSPECIFIED UNSPECIFIED UNSPECIFIED Cimarelli, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Greco, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Bertrand, Pascale UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED Buening, Hildegard UNSPECIFIED UNSPECIFIED UNSPECIFIED Salvetti, Anna UNSPECIFIED orcid.org/0000-0003-2007-8350 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-400102
DOI:	10.1128/JVI.00171-15
Journal or Publication Title:	J. Virol.
Volume:	89
Number:	13
Page Range:	S. 6824 - 6835
Date:	2015
Publisher:	AMER SOC MICROBIOLOGY
Place of Publication:	WASHINGTON
ISSN:	1098-5514
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-DAMAGE-RESPONSE; SITE-SPECIFIC INTEGRATION; TYPE-2 P5 ELEMENT; MRE11 COMPLEX; WILD-TYPE; MRE11/RAD50/NBS1 COMPLEX; MRE11-RAD50-NBS1 COMPLEX; HELPER FUNCTIONS; REPAIR PROTEINS; ATM ACTIVATION Multiple languages Virology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40010