PGM3 inhibition rewires RUVBL2-dependent DNA repair and induces a BRCAness-like state in pancreatic cancer cells
- 1University of Milano-Bicocca, Milano, Italy
Abstract
Pancreatic ductal adenocarcinoma (PDAC) exhibits profound metabolic rewiring and strong resistance to DNA-damaging therapies, yet how metabolic pathways regulate genome maintenance remains poorly understood. The hexosamine biosynthetic pathway (HBP) integrates nutrient availability with protein glycosylation through production of UDP-GlcNAc, but its role in DNA damage response (DDR) regulation is unclear. Here we show that inhibition of the HBP enzyme phosphoglucomutase-3 (PGM3) reduces DNA repair capacity in pancreatic cancer cells. Transcriptomic and functional analyses reveal that the selective PGM3 inhibitor FR054 amplifies gemcitabine-induced replication stress, disrupts ATR-CHK1 and ATM-CHK2 checkpoint signaling, and selectively impairs homologous recombination. Glycoproteomic profiling identifies the AAA+ ATPase RUVBL2 as a key metabolic-DDR node. Gemcitabine increases RUVBL2 O-GlcNAcylation, with Thr81 identified as a modified residue within the Walker A nucleotide-binding motif. Structural modelling predicts that Thr81 O-GlcNAcylation stabilizes the RUVBL1-RUVBL2 complex without compromising ATP-Mg engagement. PGM3 inhibition and Thr81 mutation similarly reduced ATR and ATM abundance and promoted persistent DNA damage, supporting a role for RUVBL2 Thr81 O-GlcNAcylation in sustaining checkpoint signalling and genome stability. Consequently, PGM3 inhibition induces a BRCAness-like state that sensitizes pancreatic cancer cells to PARP inhibition, both in vitro and in vivo, as well as to ionizing radiation. These findings reveal a nutrient-sensitive mechanism linking protein glycosylation to genome maintenance and identify HBP-dependent DNA repair as a potentially actionable vulnerability in pancreatic cancer.
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BibTeX
@misc{zerbato2026pgm3,
title = {{PGM3 inhibition rewires RUVBL2-dependent DNA repair and induces a BRCAness-like state in pancreatic cancer cells}},
author = {B. Zerbato and G. Taverna and M. La Chimia and M. Pontoriero and S. Lombardi and L. Taglietti and K. Deng and G. C. Perrone and S. Hakkola and A. Vuori and T. Syriala and E. De Billy and S. M. Barabino and C. Bragato and C. L. Pierri and B. La Ferla and A. Urbanucci and D. Scumaci and F. Chiaradonna},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.746486},
url = {https://www.biorxiv.org/content/10.64898/2026.08.31.746486v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - PGM3 inhibition rewires RUVBL2-dependent DNA repair and induces a BRCAness-like state in pancreatic cancer cells
AU - B. Zerbato
AU - G. Taverna
AU - M. La Chimia
AU - M. Pontoriero
AU - S. Lombardi
AU - L. Taglietti
AU - K. Deng
AU - G. C. Perrone
AU - S. Hakkola
AU - A. Vuori
AU - T. Syriala
AU - E. De Billy
AU - S. M. Barabino
AU - C. Bragato
AU - C. L. Pierri
AU - B. La Ferla
AU - A. Urbanucci
AU - D. Scumaci
AU - F. Chiaradonna
PY - 2026
DA - 2026/08/31
PB - bioRxiv
DO - 10.64898/2026.08.31.746486
UR - https://www.biorxiv.org/content/10.64898/2026.08.31.746486v1
AB - Pancreatic ductal adenocarcinoma (PDAC) exhibits profound metabolic rewiring and strong resistance to DNA-damaging therapies, yet how metabolic pathways regulate genome maintenance remains poorly understood. The hexosamine biosynthetic pathway (HBP) integrates nutrient availability with protein glycosylation through production of UDP-GlcNAc, but its role in DNA damage response (DDR) regulation is unclear. Here we show that inhibition of the HBP enzyme phosphoglucomutase-3 (PGM3) reduces DNA repair capacity in pancreatic cancer cells. Transcriptomic and functional analyses reveal that the selective PGM3 inhibitor FR054 amplifies gemcitabine-induced replication stress, disrupts ATR-CHK1 and ATM-CHK2 checkpoint signaling, and selectively impairs homologous recombination. Glycoproteomic profiling identifies the AAA+ ATPase RUVBL2 as a key metabolic-DDR node. Gemcitabine increases RUVBL2 O-GlcNAcylation, with Thr81 identified as a modified residue within the Walker A nucleotide-binding motif. Structural modelling predicts that Thr81 O-GlcNAcylation stabilizes the RUVBL1-RUVBL2 complex without compromising ATP-Mg engagement. PGM3 inhibition and Thr81 mutation similarly reduced ATR and ATM abundance and promoted persistent DNA damage, supporting a role for RUVBL2 Thr81 O-GlcNAcylation in sustaining checkpoint signalling and genome stability. Consequently, PGM3 inhibition induces a BRCAness-like state that sensitizes pancreatic cancer cells to PARP inhibition, both in vitro and in vivo, as well as to ionizing radiation. These findings reveal a nutrient-sensitive mechanism linking protein glycosylation to genome maintenance and identify HBP-dependent DNA repair as a potentially actionable vulnerability in pancreatic cancer.
ER -