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Preprint WatchModerateNovember 7th, 2026

PARP1-mediated PARylation of SPRTN restrains its DNA-protein crosslink repair activity

Rahman, A.; Quevedo, V.; Garcia, M.; Rhiner, A.; Simonson, Q.; Perez, E.; Lopez-Mosqueda, J.

PARP1-dependent PARylation of SPRTN acts as negative feedback restraining SPRTN DNA engagement and proteolytic activity, positioning PARP1 as an upstream regulator of DNA-protein crosslink repair and of TOP1 cleavage-complex clearance.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint advances PARP1 as a regulatory node controlling SPRTN and the clearance of TOP1 cleavage complexes, which is a cleaner mechanistic story than the clinical record supports. Claidex holds two PARP1 program failures, olaparib-pembrolizumab-parp1-metastatic-tnbc-keylynk-009-phase2-maintenance-efficacy-failure and talazoparib-temozolomide-parp1-ddr-wild-type-mcrpc-phase1b2-translational-mismatch, and the second failed precisely because DNA damage response biology that held in model systems did not select responders in a DDR wild-type population. The TOP1 arm of the same axis also has a failure on record, cbx-12-top1-phlip-exatecan-platinum-resistant-ovarian-phase2-termination. Elegant upstream regulation of repair enzymes has repeatedly failed to convert into clinical benefit without a selection biomarker, and this work does not supply one.

Abstract excerpt

SPRTN is a DNA-dependent metalloprotease that resolves DNA-protein crosslinks, but how its activity is restrained on chromatin remains unclear. Here we show that SPRTN is PARylated in a PARP1- and HPF1-dependent manner. Mass spectrometry datasets identify seven modified residues in the C-terminal region, and substituting them (SPRTN-PARless) strongly reduces PARylation. The Nudix homology domain is required for SPRTN to interact with PARP1 and for efficient PARylation. SPRTN-PARless accumulates faster and to higher levels at laser-induced DNA damage than wild-type SPRTN. PARylation reduces single-stranded DNA binding of both cell-derived and purified SPRTN, and PARG treatment reverses this effect for cell-derived protein. SPRTN-PARless shows increased autocleavage and accelerates clearance of camptotheci-induced TOP1 cleavage complexes. These findings suggest that PARylation acts as negative feedback on SPRTN after its PAR-dependent recruitment, restraining its DNA engagement and proteolytic activity.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.