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Herpes Simplex Virus type 1 replication proteins disable ATR signaling by binding to substrates that would normally recruit 9–1‐1 and topBP1 to activate ATR
Author(s) -
Weller Sandra K,
Mohni Kareem N
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.757.1
Subject(s) - single stranded binding protein , dna damage , microbiology and biotechnology , chromatin , biology , transfection , dna , phosphorylation , dna replication , dna binding protein , biochemistry , gene , transcription factor
During HSV‐1 infection, ATM but not ATR is activated leading to the phosphorylation of Chk2 but not Chk1. Furthermore, although hydroxyurea normally activates ATR, Chk1 is not phosphorylated in HU‐treated HSV‐1 infected cells. The ss DNA binding protein, ICP8, and three subunit Helicase/Primase (H/P) are required to inhibit ATR signaling. These four viral proteins are necessary and sufficient to disable ATR signaling in transfected cells. ATR is generally activated by substrates which contain ssDNA adjacent to dsDNA. ICP8 and H/P also recognize this type of substrate. We suggest that these four viral proteins prevent ATR activation by binding to the DNA substrate and obstructing loading of the Rad9‐Rad1‐Hus1 checkpoint clamp (9–1‐1). In fact, when ICP8 and H/P are expressed by transfection, the recruitment of the 9–1‐1 is prevented which in turn prevents the recruitment of TopBP1 and thus effectively disables ATR signaling. In addition, we show that 9–1‐1 becomes chromatin bound in response to DNA damaging agents in uninfected controls, but is excluded from chromatin in the presence of HSV‐1 replication proteins. The observation that viral proteins can exclude cellular DNA repair proteins from the sites of DNA damage represents a novel mechanism of ATR inhibition.