IRS-1-Rad51 nuclear interaction sensitizes JCV T-antigen positive medulloblastoma cells to genotoxic treatment.
The large T-antigen from human polyomavirus JC (JCV T-antigen) is suspected to play a role in malignant transformation. Previously, we reported that JCV T-antigen requires the presence of a functional insulin-like growth factor I receptor (IGF-IR) for transformation of fibroblasts and for survival of medulloblastoma cell lines; that IGF-IR is phosphorylated in medulloblastoma biopsies and that JCV T-antigen inhibits homologous recombination-directed DNA repair, causing accumulation of mutations. Here we are evaluating whether JCV T-antigen positive and negative mouse medulloblastoma cell lines, which significantly differ in their tumorigenic properties, are also different in their abilities to repair double strand breaks of DNA (DSBs). Our results show that despite much stronger tumorigenic potential, JCV T-antigen positive medulloblastoma cells are more sensitive to genotoxic agents (cisplatin and gamma-irradiation). Subsequent analysis of DNA repair of DSBs indicated that homologous recombination-directed DNA repair (HRR) was selectively attenuated in JCV T-antigen positive medulloblastoma cells. JCV T-antigen did not affect HRR directly. In the presence of JCV T-antigen, insulin receptor substrate 1 (IRS-1) translocated to the nucleus where it co-localized with Rad51, possibly attenuating HRR.
Center for Neurovirology, Department of Neuroscience, Temple University, Philadelphia, PA 19122, USA.
Joanna
J
Trojanek
Thu
T
Ho
Sidney
S
Croul
Jin Ying
JY
Wang
Janaki
J
Chintapalli
Mateusz
M
Koptyra
Antonio
A
Giordano
Kamel
K
Khalili
Krzysztof
K
Reiss
D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism*; D000957:Antigens, Viral, Tumor; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005720:Gamma Rays; D055504:Insulin Receptor Substrate Proteins; D000072200:Ku Autoantigen; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D051135:Rad51 Recombinase / Q000378:metabolism*
D034961:Antigens, Nuclear; D000952:Antigens, Polyomavirus Transforming; D000957:Antigens, Viral, Tumor; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D051747:DNA-Activated Protein Kinase; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen; D002945:Cisplatin