Francesca Citron, Luca Cecchetto, Elisabetta Granato, I-Lin Ho, Zhaoliang Liu, Chiara Balestrieri, Er-Yen Yen, Luigi Perelli, L. Zhang, Luis A. Castillo Montanez, Charles A. Dyke, R. S. Shah, Sergio Attanasio, Sanjana Srinivasan, Sunetra Roy, Hyuk Jean Kwon, Nicholas Blazanin, Yue Chen, Ko‐Chien Chen, Ziheng Chen, Iolanda Scognamiglio, Nhung Pham, Shan Jiang, Jing Pan, Cecilia S. Leung, L Wang, Sisi Gao, Alessandro Carugo, Huamin Wang, Wantong Yao, Giovanni Tonon, Maria Chiara Bonini, Malgorzata Anna Zal, Collene Jeter, John A Tainer, Timothy P. Heffernan, Virginia Giuliani, Yonathan Lissanu, Giannicola Genovese, Mauro Di Pilato, Andrea Viale, Katharina Schlacher, Giulio Draetta
Perturbations in DNA replication can impair fork stability, resulting in cumulative DNA replication stress. As activation of the DNA stress response elicits immunomodulatory effects, understanding the cross-talk between the epigenetic control of replication fork stability and the recruitment of immune cells may represent an actionable avenue to potentiate the sensitivity of tumors to immunotherapy. In this study, we identified DPY30, a member of the histone methyltransferase WRAD/COMPASS complex, as a replication stress-specific epigenetic modifier in pancreatic ductal adenocarcinoma (PDAC). Although other WRAD components broadly regulate transcription, DPY30 distinctively promoted H3K4me3 deposition at stressed DNA replication forks to safeguard DNA replication stability without altering global gene expression. Loss of DPY30 destabilized stalled forks causing fork degradation, chromosomal instability, and inflammation without reducing cancer cell proliferation. Consequently, T-cell infiltration induced by DPY30 deficiency promoted a tumor response to immune checkpoint blockade (ICB). In patients with PDAC, high DPY30 tumor expression was associated with poorer ICB response, underscoring the potential of DPY30 as a predictive biomarker of immunotherapy response. Together, this study redefines our understanding of a replication stress-specific epigenetic code, unveiling DPY30 as a chromatin switch essential for stressed fork stability and a potential therapeutic target. SIGNIFICANCE: Loss of DPY30, a replication stress-specific epigenetic regulator that stabilizes stressed forks, promotes genomic instability, inflammation, and immunotherapy sensitivity, highlighting DPY30 as predictive biomarker and therapeutic target in pancreatic cancer. See related commentary by Thakur and Oberdoerffer, p. 2831.