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

Author:

Yang Mingming1,Wang Chenliang1,Zhou Mi1,Bao Lei1,Wang Yanan1,Kumar Ashwani2,Xing Chao234,Luo Weibo15ORCID,Wang Yingfei167ORCID

Affiliation:

1. Department of Pathology, University of Texas Southwestern Medical Center , Dallas , TX 75390 , USA

2. Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center , Dallas , TX 75390 , USA

3. Department of Bioinformatics, University of Texas Southwestern Medical Center , Dallas , TX 75390 , USA

4. Department of Population and Data Sciences, University of Texas Southwestern Medical Center , Dallas , TX 75390 , USA

5. Department of Pharmacology, University of Texas Southwestern Medical Center , Dallas , TX 75390 , USA

6. Department of Neurology, University of Texas Southwestern Medical Center , Dallas , TX 75390 , USA

7. Peter O’Donnell Brain Institute, UT Southwestern Medical Center , Dallas , TX 75390 , USA

Abstract

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 regulator of PARthanatos. Loss of KDM6B protein or its demethylase activity conferred cancer cell 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 XRCC1-dependent 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.

Funder

National Institutes of Health

Welch foundation

University of Texas

UT Rising Stars

NIH

CRPIT

Welch Foundation

Publisher

Oxford University Press (OUP)

Subject

Genetics

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