DPY30 Is an Epigenetic Decoupler Linking Replication Stress to Immunoediting in Pancreatic Cancer
Year: 2026
Type: article
Abstract: 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.
Source: Cancer Research
Authors: Francesca Citron, Luca Cecchetto, Elisabetta Granato, I-Lin Ho, Zhaoliang Liu, Chiara Balestrieri, Er-Yen Yen, Luigi Perelli, Li Zhang, Luis A. Castillo Montanez, Charles A. Dyke, Rutvi 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, Linghua 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 F. Draetta
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: Fondazione AIRC per la ricerca sul cancro ETS, U.S. Department of Defense, American Association for Cancer Research, V Foundation for Cancer Research, Rita Allen Foundation, Cancer Prevention and Research Institute of Texas, Andrew Sabin Family Foundation, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute, National Institute of Environmental Health Sciences
Awards: BRCA Answers From Cancer Interactome Structures (BACIS), Recruitment of First-Time, Tenure-Track Faculty Members, G192126355, G2675989440, Recruitment of First-Time, Tenure-Track Faculty Members, Mechanism of RAD51C fork protection and environmental carcinogenesis, MD Anderson Cancer Center SPORE in Gastrointestinal Cancer, DISSECTING TISSUE-SPECIFIC EFFECTS OF VHL GERMLINE VARIANTS IN VON HIPPEL-LINDAU SYNDROME, G3796292726, Compound heterozygous mutations in pediatric cancer predisposition, The Future of Cancer Research: Training Program for Basic and Translational Scientists, G6471846243, Epithelial memory of resolved inflammation as a driver of pancreatic cancer progression, Genetics and Biology of Pancreatic Ductal Adenocarcinoma, Mesoscale and Nanoscale Technologies Integrated by Structures for DNA Repair Complexes (MANTIS-DRC), Mitochondrial heterogeneity as the origin of chemoresistance in pancreatic cancer, G97262289
OpenAlex ID: W7150806168