Catalytically inactive PARP1 protein drives PARP inhibitor induced hematological toxicity
- 1Columbia University
Abstract
Dual PARP1/2 inhibitors (PARPi) selectively eliminate BRCA1/2-deficient cancers and represent the first targeted therapy for homologous recombination (HR)-deficient cancers. However, their use in maintenance therapy is limited by severe anemia and an increased risk for therapy-related leukemia. These toxicities are unexpected because PARP1 loss, which eliminates most DNA-damage-induced PARylation, does not cause anemia in mice. In contrast, PARP2 loss or catalytic inactivation causes anemia, motivating the development of PARP1-selective inhibitors. Using wild-type (WT), Parp1-/- and Parp2-/- mice, we show that hematopoietic toxicity of FDA-approved PARPi is driven primarily by inactive PARP1 rather than PARP2 inhibition. Accordingly, PARP1-selective inhibitors also cause PARP1-dependent anemia. Somatic expression of catalytically inactive Parp1 (Parp1E988A) causes lethal bone marrow failure, not found with somatic deletion of both Parp1&2. Mechanistically, inactive PARP1 obstructs the repair of diverse DNA lesions, including gaps, nicks, and Top1-cc, in contrast to the nick-selectivity of Parp2. In cells, inactive PARP1 compromises PARP2 recruitment to DNA lesions and causes severe genomic instability and mitotic bridges absent in Parp1&2-null cells. Thus, PARPi-induced hematopoietic toxicity is driven primarily by PARP1 inactivation, informing the design and use of next-generation PARP inhibitors.
Related
- Glioblastoma model mouse rescue from mortality by brain-targeted catalytically-enhanced angiotensin-converting enzyme 2 mutant-antibody fusion protein
- Prosopis africana protects against heavy metal mixture-induced pulmonary and hematological toxicity via nuclear factor erythroid 2-related factor 2/ nuclear factor-kappa B/ caspase-3 signaling
- Predischarge blood count and nutritional risk marker patterns associated with 30-day unplanned readmissions for hematological toxicity after radiotherapy for nasopharyngeal carcinoma: a multicenter cohort study.
- How to prevent and manage PARP inhibitor-related hematological toxicities in prostate cancer?
- 993 Optimizing management of immune checkpoint inhibitor-mediated toxicity in cancer patients
BibTeX
@misc{lin2026catalytically,
title = {{Catalytically inactive PARP1 protein drives PARP inhibitor induced hematological toxicity}},
author = {X. Lin and Z. Shao and D. Yaneva and W. Jiang and D. Menolfi and S. K. Bhandari and B. J. Lee and M. Schmucker and F. Yaneva and A. E. Tomkinson and J. Stingele and S. Zha},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753312},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753312v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Catalytically inactive PARP1 protein drives PARP inhibitor induced hematological toxicity
AU - X. Lin
AU - Z. Shao
AU - D. Yaneva
AU - W. Jiang
AU - D. Menolfi
AU - S. K. Bhandari
AU - B. J. Lee
AU - M. Schmucker
AU - F. Yaneva
AU - A. E. Tomkinson
AU - J. Stingele
AU - S. Zha
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753312
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753312v1
AB - Dual PARP1/2 inhibitors (PARPi) selectively eliminate BRCA1/2-deficient cancers and represent the first targeted therapy for homologous recombination (HR)-deficient cancers. However, their use in maintenance therapy is limited by severe anemia and an increased risk for therapy-related leukemia. These toxicities are unexpected because PARP1 loss, which eliminates most DNA-damage-induced PARylation, does not cause anemia in mice. In contrast, PARP2 loss or catalytic inactivation causes anemia, motivating the development of PARP1-selective inhibitors. Using wild-type (WT), Parp1-/- and Parp2-/- mice, we show that hematopoietic toxicity of FDA-approved PARPi is driven primarily by inactive PARP1 rather than PARP2 inhibition. Accordingly, PARP1-selective inhibitors also cause PARP1-dependent anemia. Somatic expression of catalytically inactive Parp1 (Parp1E988A) causes lethal bone marrow failure, not found with somatic deletion of both Parp1&2. Mechanistically, inactive PARP1 obstructs the repair of diverse DNA lesions, including gaps, nicks, and Top1-cc, in contrast to the nick-selectivity of Parp2. In cells, inactive PARP1 compromises PARP2 recruitment to DNA lesions and causes severe genomic instability and mitotic bridges absent in Parp1&2-null cells. Thus, PARPi-induced hematopoietic toxicity is driven primarily by PARP1 inactivation, informing the design and use of next-generation PARP inhibitors.
ER -