PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved..
Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:4 |
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| Enthalten in: |
Cell reports. Medicine - 4(2023), 12 vom: 19. Dez., Seite 101326 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Yang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.12.2023 Date Revised 12.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1016/j.xcrm.2023.101326 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366090704 |
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| 100 | 1 | |a Li, Yang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 22.12.2023 | ||
| 500 | |a Date Revised 12.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a DNA replication stress | |
| 650 | 4 | |a PARP inhibitors | |
| 650 | 4 | |a PRMT inhibitors | |
| 650 | 4 | |a arginine methylation | |
| 650 | 4 | |a breast cancer | |
| 650 | 4 | |a ovarian cancer | |
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| 650 | 7 | |a Protein-Arginine N-Methyltransferases |2 NLM | |
| 650 | 7 | |a EC 2.1.1.319 |2 NLM | |
| 650 | 7 | |a Repressor Proteins |2 NLM | |
| 650 | 7 | |a PRMT5 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.1.1.319 |2 NLM | |
| 700 | 1 | |a Dobrolecki, Lacey E |e verfasserin |4 aut | |
| 700 | 1 | |a Sallas, Christina |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xudong |e verfasserin |4 aut | |
| 700 | 1 | |a Kerr, Travis D |e verfasserin |4 aut | |
| 700 | 1 | |a Bisht, Deepa |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yalong |e verfasserin |4 aut | |
| 700 | 1 | |a Awasthi, Sharad |e verfasserin |4 aut | |
| 700 | 1 | |a Kaundal, Babita |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Siqi |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Weiyi |e verfasserin |4 aut | |
| 700 | 1 | |a Mendillo, Marc L |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Yiling |e verfasserin |4 aut | |
| 700 | 1 | |a Jeter, Collene R |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Guang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jinsong |e verfasserin |4 aut | |
| 700 | 1 | |a Westin, Shannon N |e verfasserin |4 aut | |
| 700 | 1 | |a Sood, Anil K |e verfasserin |4 aut | |
| 700 | 1 | |a Lewis, Michael T |e verfasserin |4 aut | |
| 700 | 1 | |a Das, Jishnu |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, S Stephen |e verfasserin |4 aut | |
| 700 | 1 | |a Bedford, Mark T |e verfasserin |4 aut | |
| 700 | 1 | |a McGrail, Daniel J |e verfasserin |4 aut | |
| 700 | 1 | |a Sahni, Nidhi |e verfasserin |4 aut | |
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