Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

KDM6B sensitizes PARthanatos via suppression of O6-methylguanine DNA methyltransferase repair and sustained checkpoint response

Mingming Yang, Chenliang Wang, Mi Zhou, Lei Bao, Yanan Wang, Ashwani Kumar, View ORCID ProfileChao Xing, View ORCID ProfileWeibo Luo, View ORCID ProfileYingfei Wang
doi: https://doi.org/10.1101/2021.12.17.473255
Mingming Yang
1Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chenliang Wang
1Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mi Zhou
1Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lei Bao
1Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yanan Wang
1Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ashwani Kumar
2Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chao Xing
2Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA
3Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75390, USA
4Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX 75390, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Chao Xing
Weibo Luo
1Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
5Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Weibo Luo
Yingfei Wang
1Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
6Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390, USA
7Peter O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA
8Cecil H. and Ida Green Center for Reproductive Biology Sciences, UT Southwestern Medical Center, Dallas, TX 75390, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Yingfei Wang
  • For correspondence: yingfei.wang@utsouthwestern.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA damage sensor and contributes to both DNA repair and cell death processes. However, how PARP-1 signaling is regulated to switch its function from DNA repair to cell death remains largely unknown. Here, we found that PARP-1 plays a central role in alkylating agent-induced PARthanatic cancer cell death. Lysine demethylase 6B (KDM6B) was identified as a key cell death effector in PARthanatos. Knockout of KDM6B or loss of KDM6B demethylase activity conferred cancer cells resistance to PARthanatic cell death in response to alkylating agents. Mechanistically, KDM6B knockout suppressed methylation at the promoter of O6-methylguanine-DNA methyltransferase (MGMT) to enhance MGMT expression and its direct DNA repair function, thereby inhibiting DNA damage-evoked PARP-1 hyperactivation and subsequent cell death. Moreover, KDM6B knockout triggered sustained Chk1 phosphorylation and activated a second repair machinery to fix DNA damage evading from MGMT repair. Inhibition of MGMT or checkpoint response re-sensitized KDM6B deficient cells to PARthanatos induced by alkylating agents. These findings provide new molecular insights into epigenetic regulation of PARP-1 signaling mediating DNA repair or cell death and identify KDM6B as a biomarker for prediction of cancer cell vulnerability to alkylating agent treatment.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted December 18, 2021.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
KDM6B sensitizes PARthanatos via suppression of O6-methylguanine DNA methyltransferase repair and sustained checkpoint response
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
KDM6B sensitizes PARthanatos via suppression of O6-methylguanine DNA methyltransferase repair and sustained checkpoint response
Mingming Yang, Chenliang Wang, Mi Zhou, Lei Bao, Yanan Wang, Ashwani Kumar, Chao Xing, Weibo Luo, Yingfei Wang
bioRxiv 2021.12.17.473255; doi: https://doi.org/10.1101/2021.12.17.473255
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
KDM6B sensitizes PARthanatos via suppression of O6-methylguanine DNA methyltransferase repair and sustained checkpoint response
Mingming Yang, Chenliang Wang, Mi Zhou, Lei Bao, Yanan Wang, Ashwani Kumar, Chao Xing, Weibo Luo, Yingfei Wang
bioRxiv 2021.12.17.473255; doi: https://doi.org/10.1101/2021.12.17.473255

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Molecular Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3586)
  • Biochemistry (7545)
  • Bioengineering (5495)
  • Bioinformatics (20732)
  • Biophysics (10294)
  • Cancer Biology (7951)
  • Cell Biology (11610)
  • Clinical Trials (138)
  • Developmental Biology (6586)
  • Ecology (10168)
  • Epidemiology (2065)
  • Evolutionary Biology (13580)
  • Genetics (9521)
  • Genomics (12817)
  • Immunology (7906)
  • Microbiology (19503)
  • Molecular Biology (7641)
  • Neuroscience (41982)
  • Paleontology (307)
  • Pathology (1254)
  • Pharmacology and Toxicology (2192)
  • Physiology (3259)
  • Plant Biology (7025)
  • Scientific Communication and Education (1294)
  • Synthetic Biology (1947)
  • Systems Biology (5419)
  • Zoology (1113)