PMID- 21589897
OWN - NLM
STAT- MEDLINE
DCOM- 20121009
LR  - 20211203
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 7
IP  - 5
DP  - 2011 May
TI  - An E2F1-mediated DNA damage response contributes to the replication of human 
      cytomegalovirus.
PG  - e1001342
LID - 10.1371/journal.ppat.1001342 [doi]
LID - e1001342
AB  - DNA damage resulting from intrinsic or extrinsic sources activates DNA damage 
      responses (DDRs) centered on protein kinase signaling cascades. The usual 
      consequences of inducing DDRs include the activation of cell cycle checkpoints 
      together with repair of the damaged DNA or induction of apoptosis. Many DNA 
      viruses elicit host DDRs during infection and some viruses require the DDR for 
      efficient replication. However, the mechanism by which DDRs are activated by 
      viral infection is poorly understood. Human cytomegalovirus (HCMV) infection 
      induces a DDR centered on the activation of ataxia telangiectasia mutated (ATM) 
      protein kinase. Here we show that HCMV replication is compromised in cells with 
      inactivated or depleted ATM and that ATM is essential for the host DDR early 
      during infection. Likewise, a downstream target of ATM phosphorylation, H2AX, 
      also contributes to viral replication. The ATM-dependent DDR is detected as 
      discrete, nuclear gammaH2AX foci early in infection and can be activated by IE 
      proteins. By 24 hpi, gammaH2AX is observed primarily in HCMV DNA replication 
      compartments. We identified a role for the E2F1 transcription factor in mediating 
      this DDR and viral replication. E2F1, but not E2F2 or E2F3, promotes the 
      accumulation of gammaH2AX during HCMV infection or IE protein expression. Moreover, 
      E2F1 expression, but not the expression of E2F2 or E2F3, is required for 
      efficient HCMV replication. These results reveal a novel role for E2F1 in 
      mediating an ATM-dependent DDR that contributes to viral replication. Given that 
      E2F activity is often deregulated by infection with DNA viruses, these 
      observations raise the possibility that an E2F1-mediated mechanism of DDR 
      activation may be conserved among DNA viruses.
FAU - E, Xiaofei
AU  - E X
AD  - Department of Microbiology and Physiological Systems, University of Massachusetts 
      Medical School, Worcester, Massachusetts, United States of America.
FAU - Pickering, Mary T
AU  - Pickering MT
FAU - Debatis, Michelle
AU  - Debatis M
FAU - Castillo, Jonathan
AU  - Castillo J
FAU - Lagadinos, Alexander
AU  - Lagadinos A
FAU - Wang, Shixia
AU  - Wang S
FAU - Lu, Shan
AU  - Lu S
FAU - Kowalik, Timothy F
AU  - Kowalik TF
LA  - eng
GR  - P30 DK032520/DK/NIDDK NIH HHS/United States
GR  - R01 AI076189/AI/NIAID NIH HHS/United States
GR  - 5 P30 DK32520/DK/NIDDK NIH HHS/United States
GR  - R01AI076189/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110512
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA, Viral)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (E2F1 Transcription Factor)
RN  - 0 (E2F1 protein, human)
RN  - 0 (H2AX protein, human)
RN  - 0 (Histones)
RN  - 0 (IE1 protein, cytomegalovirus)
RN  - 0 (IE2 protein, Cytomegalovirus)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Trans-Activators)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 3G6A5W338E (Caffeine)
RN  - EC 2.7.11.1 (ATM protein, human)
RN  - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Ataxia Telangiectasia Mutated Proteins
MH  - Caffeine/pharmacology
MH  - Cell Cycle Proteins/*genetics/metabolism
MH  - Cell Line
MH  - Cytomegalovirus/genetics/growth & development/*physiology
MH  - Cytomegalovirus Infections/*virology
MH  - *DNA Damage
MH  - DNA Repair/physiology
MH  - DNA, Viral/biosynthesis/genetics
MH  - DNA-Binding Proteins/*genetics/metabolism
MH  - E2F1 Transcription Factor/genetics/*metabolism
MH  - Fibroblasts/cytology/metabolism/virology
MH  - Fluorescent Antibody Technique
MH  - Histones/metabolism
MH  - Humans
MH  - Immediate-Early Proteins/metabolism
MH  - Immunoblotting
MH  - Phosphodiesterase Inhibitors/pharmacology
MH  - Protein Serine-Threonine Kinases/*genetics/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Signal Transduction
MH  - Trans-Activators/metabolism
MH  - Tumor Suppressor Proteins/*genetics/metabolism
MH  - Virus Replication/*physiology
PMC - PMC3093362
COIS- The authors have declared that no competing interests exist.
EDAT- 2011/05/19 06:00
MHDA- 2012/10/10 06:00
PMCR- 2011/05/12
CRDT- 2011/05/19 06:00
PHST- 2010/07/16 00:00 [received]
PHST- 2011/04/11 00:00 [accepted]
PHST- 2011/05/19 06:00 [entrez]
PHST- 2011/05/19 06:00 [pubmed]
PHST- 2012/10/10 06:00 [medline]
PHST- 2011/05/12 00:00 [pmc-release]
AID - 10-PLPA-RA-3789R2 [pii]
AID - 10.1371/journal.ppat.1001342 [doi]
PST - ppublish
SO  - PLoS Pathog. 2011 May;7(5):e1001342. doi: 10.1371/journal.ppat.1001342. Epub 2011 
      May 12.