Mislocalization of the MRN complex prevents ATR signaling during adenovirus infection.

The protein kinases ataxia-telangiectasia mutated (ATM) and ATM-Rad3 related (ATR) are activated in response to DNA damage, genotoxic stress and virus infections. Here we show that during infection with wild-type adenovirus, ATR and its cofactors RPA32, ATRIP and TopBP1 accumulate at viral replication centres, but there is minimal ATR activation. We show that the Mre11/Rad50/Nbs1 (MRN) complex is recruited to viral centres only during infection with adenoviruses lacking the early region E4 and ATR signaling is activated.

Adenovirus type 5 E4orf3 protein targets the Mre11 complex to cytoplasmic aggresomes.

Virus infections have dramatic effects on structural and morphological characteristics of the host cell. The gene product of open reading frame 3 in the early region 4 (E4orf3) of adenovirus serotype 5 (Ad5) is involved in efficient replication and late protein synthesis. During infection with adenovirus mutants lacking the E4 region, the viral genomic DNA is joined into concatemers by cellular DNA repair factors, and this requires the Mre11/Rad50/Nbs1 complex.

Serotype-specific reorganization of the Mre11 complex by adenoviral E4orf3 proteins.

The early transcriptional region 4 (E4) of adenovirus type 5 (Ad5) encodes gene products that modulate splicing, apoptosis, transcription, DNA replication, and repair pathways. Viruses lacking both E4orf3 and E4orf6 have a severe replication defect, partially characterized by the formation of genome concatemers. Concatemer formation is dependent upon the cellular Mre11 complex and is prevented by both the E4orf3 and E4orf6 proteins.

Variant XRCC3 implicated in cancer is functional in homology-directed repair of double-strand breaks.

Polymorphisms in DNA repair genes, including double-strand break (DSB) repair genes, are postulated to confer increased cancer risk. A variant of the XRCC3 gene, which is involved in DSB repair, has been associated with increased risk of malignant skin melanoma and bladder cancer. We tested the hypothesis that this variant, Thr241Met, may affect cancer risk by disrupting a critical function of XRCC3, i.