Herpes simplex virus type I disrupts the ATR-dependent DNA-damage response during lytic infection

Abstract

Like other DNA viruses, herpes simplex virus type 1 (HSV-1) interacts with components of the cellular response to DNA damage. For example, HSV-1 sequesters endogenous, uninduced, hyperphosphorylated RPA (replication protein A) away from viral replication compartments. RPA is a ssDNA-binding protein that signals genotoxic stress through the ATR (ataxia telangiectasia-mutated and Rad3-related) pathway. The sequestration of endogenous hyperphosphorylated RPA away from replicating viral DNA suggests that HSV-1 prevents the normal ATRsignaling response. In this study we examine the spatial distribution of endogenous hyperphosphorylated RPA with respect to ATR, its recruitment factor, ATRIP, and the cellular dsDNA break marker, ␥ ␥H2AX, during HSV-1 infection. The accumulation of these repair factors at DNA lesions has previously been identified as an early event in signaling genotoxic stress. We show that HSV-1 infection disrupts the ATR pathway by a mechanism that prevents the recruitment of repair factors, spatially uncouples ATRIP from ATR and sequesters ATRIP and endogenous hyperphosphorylated RPA within virus-induced nuclear domains containing molecular chaperones and components of the ubiquitin proteasome. The HSV-1 immediate early protein ICP0 is sufficient to induce the redistribution of ATRIP. This is the first report that a virus can disrupt the usually tight colocalization of ATR and ATRIP.

Adenovirus 12 E4orf6 inhibits ATR activation by promoting TOPBP1 degradation

“…It is interesting to note that ATR activation is inhibited during infection not only by Ad, but also other viruses. HSV-1 ICP0, for example, promotes uncoupling of ATR and ATRIP during infection (27). It is unclear why ATR activation is detrimental to viral infection, as it does not interfere with Ad5 DNA replication (28).…”

Adenovirus DNA is detected at increased frequency in Guthrie cards from children who develop acute lymphoblastic leukaemia

“…The hallmark genetic mutations, notably translocations, of childhood ALL arise when repair of DNA breaks is faulty or inhibited. Infection with some DNA viruses, notably herpesviruses and adenoviruses, interferes with cellular DNA repair mechanisms (Weitzman and Ornelles, 2005;Wilkinson and Weller, 2006) and could lead to these characteristic genetic changes. To determine whether a prenatal virus infection could lead to the development of pre-leukaemic cells containing characteristic translocations, a correlation is sought between detection of viral DNA in Guthrie cards and the eventual development of leukaemia.…”

Interactions Between AAV-2 and HSV-1: Implications for Hybrid Vector Design

“…However, in the absence of replicating HSV-1 DNA (i.e., in the presence of transfected HSV-1 helper factors), ICP4 was recruited into AAV-2 RCs, suggesting that ICP4 may also show weak binding to AAV-2 DNA [138]. Finally, RPA was shown to be hyperphosphorylated and recruited into AAV-2 RCs [148], while hyperphosphorylation of RPA was not induced during HSV-1 replication and the low levels of endogenous hyper phosphorylated RPA were spatially excluded from HSV-1 RCs by sequestration into virus-induced chaperoneenriched domains [155,156]. RPA is a heterotrimeric ssDNA-binding protein consisting of 70-, 32-and 14-kDa subunits involved in diverse processes such as DNA replication, DNA repair, recombination and DNA damage signaling [157].…”