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Global Genome Demethylation Causes Transcription-Associated DNA Double Strand Breaks in HPV-Associated Head and Neck Cancer Cells

Hajek, Michael and Biktasova, Asel and Sewell, Andrew and Gary, Cyril and Cantalupo, Paul and Anderson, Karen S. and Yarbrough, Wendell G. and Issaeva, Natalia (2020) Global Genome Demethylation Causes Transcription-Associated DNA Double Strand Breaks in HPV-Associated Head and Neck Cancer Cells. Cancers, 13 (1). p. 21. ISSN 2072-6694

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Abstract

High levels of DNA methylation at CpG loci are associated with transcriptional repression of tumor suppressor genes and dysregulation of DNA repair genes. Human papilloma virus (HPV)-associated head and neck squamous cell carcinomas (HNSCC) have high levels of DNA methylation and methylation has been associated with dampening of an innate immune response in virally infected cells. We have been exploring demethylation as a potential treatment in HPV+ HNSCC and recently reported results of a window clinical trial showing that HNSCCs are particularly sensitive to demethylating agent 5-azacytidine (5-aza). Mechanistically, sensitivity is partially due to downregulation of HPV genes expression and restoration of tumor suppressors p53 and Rb. Here, for the first time, we show that 5-azaC treatment of HPV+ HNSCC induces replication and transcription-associated DNA double strand breaks (DSBs) that occur preferentially at demethylated genomic DNA. Blocking replication or transcription prevented formation of DNA DSBs and reduced sensitivity of HPV-positive head and neck cancer cells to 5-azaC, demonstrating that both replication and active transcription are required for formation of DSBs associated with 5-azaC.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hajek, Michael
Biktasova, Asel
Sewell, Andrew
Gary, Cyril
Cantalupo, Paulpgc92@pitt.edupgc920000-0003-3966-8481
Anderson, Karen S.
Yarbrough, Wendell G.
Issaeva, Natalia
Date: 23 December 2020
Date Type: Publication
Journal or Publication Title: Cancers
Volume: 13
Number: 1
Publisher: MDPI AG
Page Range: p. 21
DOI or Unique Handle: 10.3390/cancers13010021
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Refereed: Yes
Uncontrolled Keywords: head and neck cancer, HPV, demethylation, DNA double strand breaks, transcription, replication
ISSN: 2072-6694
Official URL: http://dx.doi.org/10.3390/cancers13010021
Funders: National Institutes of Health, National Center for Advancing Translational Science
Article Type: Research Article
Date Deposited: 04 Jun 2021 17:21
Last Modified: 04 Jun 2021 17:21
URI: http://d-scholarship.pitt.edu/id/eprint/41256

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