Possemato Lab

Publications

Papers from the lab

Key Publications

Targeting DNA Polymerase Epsilon Leads to Tumor Clearance and Activation of an NF-κB-mediated inflammatory response in Triple Negative Breast Cancer

Sher EF, Fujihara KM, Tao A, Sastourne-Haletou P, Erenburg D, Sviderskiy VO, Mir H, Karakousi TR, Loomis C, Deng J, Ruggles KV, Wong KK, Possemato R. Cancer Research. 2026 Apr 21. doi: 10.1158/0008-5472.CAN-25-2217.  View article

Suppressing the DNA polymerase epsilon catalytic subunit (POLE) induces a potent, TNBC-specific gene expression signature enriched in NF-κB-driven inflammatory cytokines, with TNBC cells showing markedly higher DNA damage and canonical NF-κB activation than luminal breast cancer cells. POLE suppression in an in vivo murine TNBC model led to cancer cell-intrinsic tumor clearance and increased immune cell infiltration, suggesting a therapeutic avenue for targeting POLE in TNBC.

Iron Overload Suppresses LKB1 and Induces IL36G Anti-Tumor Immunity in PDAC metastasis

Biancur DE, Venkatesh H, Crawford A, Jeong Y, Sohn ASW, Kapner KS, Yamamoto K, Lin EY, Banh RS, Assi M, Shapiro B, Yu P, Song SC, Coetzee WA, Aguirre AJ, Jones AN, Kimmelman AC, Possemato R. Science Advances. 2026 Jul 17;12(29):eadz8681. doi: 10.1126/sciadv.adz8681.  View article

In a CRISPR screen modeling pancreatic cancer liver metastasis, ferritin heavy chain (FTH1) emerged as the most prominent liver-specific dependency. FTH1 loss disrupts iron handling and triggers mitochondrial dysfunction and ionic imbalance, activating anti-tumor immunity mediated by the cytokine IL36G — mechanistically linked to reduced LKB1 protein levels via an RNA G-quadruplex in its 5′-UTR.

Allosteric regulation of CAD modulates de novo pyrimidine synthesis during the cell cycle

Shin J, Mir H, Khurram MA, Fujihara KM, Dynlacht BD, Cardozo TJ, Possemato R. Nat Metab. 2023 Feb 6. doi: 10.1038/s42255-023-00735-9.  View article

Reports the mechanism by which human de novo pyrimidine biosynthesis is allosterically regulated during the cell cycle, identifying two Animalia-specific loops in the CAD allosteric domain that sense and bind UTP, an allosteric inhibitor, and a signal transmission loop that controls formation of a catalytic substrate channel.

Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that can be Exploited by Targeting DNA Polymerase Epsilon

Sviderskiy VO, Blumenberg L, Gorodetsky E, Karakousi TR, Hirsh N, Alvarez SW, Terzi EM, Kaparos E, Whiten GC, Ssebyala S, Tonzi P, Mir H, Neel BG, Huang TT, Adams S, Ruggles KV, Possemato R. Molecular Cell. 2020 Nov 19; 80:1–17.  View article

  • Basal-like breast cancer (BLBC) cells are especially sensitive to suppression of iron-sulfur cluster (ISC) biosynthesis.
  • POLE1 requires ISC cofactor binding to support replication; BLBC is selectively susceptible to its partial suppression.
  • Hyperactive CDK2 may underlie BLBC's sensitivity to ISC or POLE1 suppression, and represents a targetable liability.

Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5

Terzi EM, Sviderskiy VO, Alvarez SW, Whiten GC, Possemato R. Science Advances. 2021 May 26;7(22):eabg4302.  View article

  • Most breast and lung cancer cell lines initiate an iron-starvation response upon ISC synthesis inhibition, increasing ferroptosis sensitivity.
  • IRP2 stability upon ISC inhibition depends on environmental oxygen, independent of IRP1.
  • Cells lacking both IRP1 and IRP2 are resistant to ferroptosis even when ISC synthesis is inhibited.

NFS1 Undergoes Positive Selection in Lung Tumors and Protects Cells From Elevated Oxygen Levels and Ferroptosis

Alvarez SW*, Sviderskiy VO*, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, Sabatini DM, Birsoy K, Possemato R. Nature. 2017 Nov 30.  View article

  • NFS1, a critical enzyme in iron-sulfur cluster cofactor biosynthesis, is upregulated in lung adenocarcinoma and under high oxygen.
  • Suppressing ISC biosynthesis activates the iron-starvation response and increases sensitivity to ferroptosis.

Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs

Minton DR, Nam M, McLaughlin DJ, Shin J, Bayraktar EC, Alvarez SW, Sviderskiy VO, Papagiannakopoulos T, Sabatini DM, Birsoy K, Possemato R. Mol Cell. 2018 Feb 15;69(4):610–621.  View article

Mitochondrial one-carbon metabolism harvests carbon units from serine, supporting both nucleotide synthesis and formylation of the mitochondrial initiator tRNA. Complete loss of this pathway impairs mitochondrial translation and oxidative phosphorylation, which a parallel cytoplasmic pathway cannot rescue.

Selected Publications

* denotes equal contribution.

Selected Reviews