Viruses And DDR Flashcards
Describe adenoviruses in association with DDR
dsDNA viruses with a linear genome
Generally seen to disable the damage response by the degradation of cellular DDR proteins eg p53, Mre11, TOPBP1, DNA ligase4, BLM and DAXX
E1B-55K targets the proteins for degradation using an E3 ligase to add ubiquitins that target it to a proteosome
Ad5 utilises Cul5 in its ubiquitin ligase and Ad12 utilises Cul2
And degradation of TopBP1 by Ad12 is E1B-54K independent
What proteins are shown to relocalise in the nucleus during Ad infection?
RPA32 and ATRIP RPA32 and Rad17 Rad9 and RPA32 TopBP1 and RPA32 DDR proteins relocate to nuclear bodies and into aggressomes in the cytoplasm
Describe the proteins degrade during adenovirus invasion
p53- TF activated in response to DNA damage
Mre11- part of the MRN complex involved in HR
BLM- protein DNA helicase involved in HR
DNA ligase4- joins DSB in NHEJ
TopBP1- topoisomerase 2beta binding protein involved in the activation of ATR
DAXX- multifunctional protein associated with heterochromatin
Describe SV40 and the DDR
Simian virus 40 requires DDR activity to replicate
SV40T antigen is phosphorylated by ATM and is essential for optimal viral replication- binds to NBS1 and this may cause endo-replication giving rise to multiple copies of the genome in SV40 infected cells
But there is also Mre11 degradation in SV40 infected cells
Various proteins eg. FANCD2, MRN complex, ATM and phosphorylated-H1AX, are recruited to viral replication centres
How else can some viruses damage DNA?
Induce genomic instability
Can introduce chromosomal breaks
Eg. Adenovirus 12, heroes simplex virus (HSV), Epstein-Barr virus (EBV), cytomegalovirus (CMV)
HSV causes ‘pulverisation’ at late times of infection attributed to viral polymerases and nucleases
What has EBV been linked to?
Cancers like Burkitt's lymphoma Hodgkin's lymphoma Nasopharyngeal carcinoma Gastric cancer T cell lymphoma Post-Transplant lymphoproliferative disease (PTLD) As DNA damage response and apoptosis is inactivated
What EBV proteins have been associated differencing effects in the DDR?
LMP1- induce micronucleus formation and inhibit repair
EBNA1- induces ROS and chromosomal damage
BALF3- induced DNA strand breaks
BGLF5- induced ds breaks
BGLF4- activates DDR and delays S phase progression
What DDR proteins are involved in EBV infection?
H2AX, CHK2, p53 are phosphorylated
Phosphorylated ATM, NBS1 and Mre11 are located at the viral replication centres and Mre11 and NBS1 contribute to viral genome replication
Mismatch repair proteins and HR proteins locate to viral replication centres
Depletion of RPA, 53BP1 and Rad52 inhibits viral replication as does inhibition of ATM
Describe the effects of reactive oxygen species
One of the main causes of mutations
Can cause bulky and non-bulky base modifications, abasic sites, non-conventional SSBs, protein-DNA adducts and DNA cross links
How does HCV induce oxidative stress?
Viral proteins activate oncogene c-Myc
Through inflammation
Symptoms of infection
Directly
Describe RNA viruses and the DDR
Generally less activation of the DDR probably because they replicate I the cytoplasm
Major activation by retroviruses such integrate cDNA into the host genome axis ring genomic instability
Human hepatitis C virus cause generation of ROS
What are the proposed relationships between viruses and DDR?
The cell could recognise the viral DNA as just broken DNA triggering the response
It could form a part of the antiviral response
Stree caused by the virus invading the host cell could trigger the response
The virus might intentionally activate DDR as it could aid the vital replication process
