Viral Interference with DNA Repair by Targeting of the Single-Stranded DNA Binding Protein RPA: e1003725

Correct repair of damaged DNA is critical for genomic integrity. Deficiencies in DNA repair are linked with human cancer. Here we report a novel mechanism by which a virus manipulates DNA damage responses. Infection with murine polyomavirus sensitizes cells to DNA damage by UV and etoposide. Polyoma...

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Bibliographic Details
Published in:PLoS pathogens 2013-10, Vol.9 (10)
Main Authors: Banerjee, Pubali, deJesus, Rowena, Gjoerup, Ole, Schaffhausen, Brian S
Format: Article
Language:English
Subjects:
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Murine polyomavirus
Mutation
Polyomavirus
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Summary:Correct repair of damaged DNA is critical for genomic integrity. Deficiencies in DNA repair are linked with human cancer. Here we report a novel mechanism by which a virus manipulates DNA damage responses. Infection with murine polyomavirus sensitizes cells to DNA damage by UV and etoposide. Polyomavirus large T antigen (LT) alone is sufficient to sensitize cells 100 fold to UV and other kinds of DNA damage. This results in activated stress responses and apoptosis. Genetic analysis shows that LT sensitizes via the binding of its origin-binding domain (OBD) to the single-stranded DNA binding protein replication protein A (RPA). Overexpression of RPA protects cells expressing OBD from damage, and knockdown of RPA mimics the LT phenotype. LT prevents recruitment of RPA to nuclear foci after DNA damage. This leads to failure to recruit repair proteins such as Rad51 or Rad9, explaining why LT prevents repair of double strand DNA breaks by homologous recombination. A targeted intervention directed at RPA based on this viral mechanism could be useful in circumventing the resistance of cancer cells to therapy.
ISSN:1553-7366
1553-7374
DOI:10.1371/journal.ppat.1003725