Alterations of DNA damage repair pathways resulting from JCV infection.
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disorder of the CNS caused by infection of glial cells with the polyomavirus, JCV. Here we report that genomic stability and DNA repair are significantly dysregulated by JCV infection of human astrocytes. Metaphase spreads exhibited increased ploidy correlating with duration of infection. Increased micronuclei formation and phospho-Histone2AX expression also indicated DNA damage. Western blot analysis revealed perturbation in expression of some DNA repair proteins including a large elevation of Rad51. Immunohistochemistry on clinical samples of PML showed robust labeling for Rad51 in nuclei of bizarre astrocytes and inclusion body-bearing oligodendrocytes that are characteristic of JCV infection. Finally, in vitro end-joining DNA repair was altered in extracts prepared from JCV-infected human astrocytes. Alterations in DNA repair pathways may be important for the life cycle of JCV and the pathogenesis of PML.
Darbinyan
Armine
A
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA 19122, USA.
White
Martyn K
MK
Akan
Selma
S
Radhakrishnan
Sujatha
S
Del Valle
Luis
L
Amini
Shohreh
S
Khalili
Kamel
K
D000328:Adult; D001253:Astrocytes / Q000378:metabolism / Q000821:virology; D001483:Base Sequence; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D042822:Genomic Instability; D006801:Humans; D007577:JC Virus / Q000472:pathogenicity / Q000502:physiology; D007968:Leukoencephalopathy, Progressive Multifocal / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D051135:Rad51 Recombinase / Q000378:metabolism
D004247:DNA; C495153:RAD51 protein, human; D051135:Rad51 Recombinase