Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency
Date
2019
Authors
Han, M.
Napier, C.E.
Frolich, S.
Teber, E.
Wong, T.
Noble, J.R.
Choi, E.H.Y.
Everett, R.D.
Cesare, A.J.
Reddel, R.R.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Journal of Cell Science, 2019; 132(5):jcs222349-1-jcs222349-10
Statement of Responsibility
Mingqi Han, Christine E. Napier, Sonja Frölich, Erdahl Teber, Ted Wong, Jane R. Noble, Eugene H.Y. Choi, Roger D. Everett, Anthony J. Cesare, and Roger R. Reddel
Conference Name
Abstract
Cancers that utilize the alternative lengthening of telomeres (ALT) mechanism for telomere maintenance are often difficult to treat and have a poor prognosis. They are also commonly deficient for expression of ATRX protein, a repressor of ALT activity, and a component of promyelocytic leukemia nuclear bodies (PML NBs) that are required for intrinsic immunity to various viruses. Here, we asked whether ATRX deficiency creates a vulnerability in ALT cancer cells that could be exploited for therapeutic purposes. We showed in a range of cell types that a mutant herpes simplex virus type 1 (HSV-1) lacking ICP0, a protein that degrades PML NB components including ATRX, was ten- to one thousand-fold more effective in infecting ATRX-deficient cells than wild-type ATRX-expressing cells. Infection of co-cultured primary and ATRX-deficient cancer cells revealed that mutant HSV-1 selectively killed ATRX-deficient cells. Sensitivity to mutant HSV-1 infection also correlated inversely with PML protein levels, and we showed that ATRX upregulates PML expression at both the transcriptional and post-transcriptional levels. These data provide a basis for predicting, based on ATRX or PML levels, which tumors will respond to a selective oncolytic herpesvirus.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 2019. Published by The Company of Biologists Ltd