Abstract
DNA repair dysregulation is a key driver of cancer development. Understanding the molecular mechanisms underlying DNA repair dysregulation in cancer cells is crucial for cancer development and therapies. Here, we report that enhancer of zeste homolog 2 (EZH2) directly methylates poly(adenosine diphosphate–ribose) polymerase-1 (PARP-1), an essential enzyme involved in DNA repair, and regulates its activity. Functionally, EZH2-catalyzed methylation represses PARP1 catalytic activity, down-regulates the recruitment of x-ray repair cross-complementing group-1 to DNA lesions and its associated DNA damage repair; on the other hand, it protects the cells from nicotinamide adenine dinucleotide overconsumption upon DNA damage formation. Meanwhile, EZH2-mediated methylation regulates PARP1 transcriptional and oncogenic activity, at least in part, through impairing PARP1-E2F1 interaction and E2F1 transcription factor activity. EZH2 and PARP1 inhibitors synergistically suppress prostate cancer growth. Collectively, our findings uncover an insight of EZH2 functions in fine-tuning PARP1 activity during DNA damage repair and cancer progression, which provides a rationale for combinational targeting EZH2 and PARP1 in cancer.
| Original language | English (US) |
|---|---|
| Article number | eadl2804 |
| Journal | Science Advances |
| Volume | 10 |
| Issue number | 48 |
| DOIs | |
| State | Published - Nov 29 2024 |
Funding
We are grateful to S. Zha for providing PARP1 cas9 knockout U2OS cell lines. We appreciate W. Kaelin and J. Yu for providing plasmids. imaging work was performed at the Northwestern University center for Advanced Microscopy generously supported by Nci ccSG P30 cA060553 awarded to the Robert h. lurie comprehensive cancer center. this work was supported by a start-up fund provided by Northwestern University (to Q.c.), Polsky Urologic cancer institute of the Robert h. lurie comprehensive cancer center of Northwestern University at Northwestern Memorial hospital (to Q.c. and R.Y.), US department of defense (W81XWh-20-1-0504 and W81XWh-17-1-0357 to Q.c.), National institutes of health/National cancer institute (R01cA208257 to Q.c., R01cA256741 to Q.c. and K.c., R01cA285684 to Q.c. and h.N., and Prostate SPORe P50cA180995 development Research Program to Q.c.), National institutes of health (GM152207 to h.N.), American cancer Society Research Scholar Award (RSG-21-013-01-dMc to h.N.), National institutes of health (R01cA259388, R35GM142441, and Prostate SPORe P50cA180995 to R.Y.), National institutes of health (R01GM138407 and R01GM125632 to K.c.), and US department of defense (W81XWh-21-1-0146, ht9425-23-1-0491 to Y. Yang). Acknowledgments: We are grateful to S. Zha for providing PARP1 cas9 knockout U2OS cell lines. We appreciate W. Kaelin and J. Yu for providing plasmids. imaging work was performed at the Northwestern University center for Advanced Microscopy generously supported by Nci ccSG P30 cA060553 awarded to the Robert h. lurie comprehensive cancer center. Funding: this work was supported by a start-up fund provided by Northwestern University (to Q.c.), Polsky Urologic cancer institute of the Robert h. lurie comprehensive cancer center of Northwestern University at Northwestern Memorial hospital (to Q.c. and R.Y.), US department of defense (W81XWh-20-1-0504 and W81XWh-17-1-0357 to Q.c.), National institutes of health/National cancer institute (R01cA208257 to Q.c., R01cA256741 to Q.c. and K.c., R01cA285684 to Q.c. and h.N., and Prostate SPORe P50cA180995 development Research Program to Q.c.), National institutes of health (GM152207 to h.N.), American cancer Society Research Scholar Award (RSG-21-013-01-dMc to h.N.), National institutes of health (R01cA259388, R35GM142441, and Prostate SPORe P50cA180995 to R.Y.), National institutes of health (R01GM138407 and R01GM125632 to K.c.), and US department of defense (W81XWh-21-1-0146, ht9425-23-1-0491 to Y. Yang). Author contributions: conceptualization: Q.M., J.S., h.N., and Q.c. Methodology: Q.M., J.S., Y.Yi., h.N., and Q.c. investigation: Q.M., J.S., Q.liu., R.W., W.J., Q.W., Y.Z., J.c.t., t.W., c.Y., and Y. Yang. visualization: Q.M., J.S., J.c.t., c.h., h.N., and Q.c. validation: Q.M., J.S., Q. liu, Q. li, c.h., h.N., and Q.c. Software: t.W., Y.l., and Q. li. Formal analysis: Q.M., J.S., Y.R., W.J., X.l., t.W., Y.l., and d.Z. data curation: Q.M., J.S., t.W., and K.c. Resources: Q.M., Q. liu, Q. li, t.W., Y.l., c.h., S.K., K.c., h.N., and Q.c. Supervision: Q.M., K.c., R.Y., h.N., and Q.c. Project administration: Q.M., J.S., K.c., h.N., and Q.c. Funding acquisition: K.c., h.N., and Q.c. Writing\u2014original draft: Q.M., J.S., Q. li, h.N., and Q.c. Writing\u2014review and editing: Q.M., J.S., K.c., h.N., and Q.c. Competing interests: the authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. the RNA-seq data generated by this study have been deposited in the GeO under accession no. GSe239560. the newly created materials supporting the findings of this study can be provided by the corresponding authors pending scientific review and a completed material transfer agreement. Requests for the related materials should be submitted to: [email protected].
ASJC Scopus subject areas
- General
