ArticleScience advances2026
LIPT1 loss confers replication stress and PARP inhibitor sensitivity through PrimPol-mediated ssDNA gaps.
Article in Science advances, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Replication stress (RS) and altered metabolism are two hallmarks of cancer, yet how metabolic perturbations contribute to RS remains poorly understood. Lipotransferase 1 (LIPT1) catalyzes the covalent attachment of lipoic acid to mitochondrial 2-ketoacid dehydrogenases, sustaining flux through the tricarboxylic acid (TCA) cycle. Loss of LIPT1 causes accumulation of 2-hydroxyglutarate (2-HG), which is known to inhibit α-ketoglutarate (α-KG)-dependent histone demethylases and promotes heterochromatin formation. Here, we show that 2-HG-driven heterochromatin impedes replication fork progression, causing fork stalling and RS in LIPT1-deficient cancer cells. To bypass stalled forks, PrimPol-mediated repriming resumes DNA synthesis but leaves behind single-stranded DNA (ssDNA), which requires poly(adenosine 5'-diphosphate-ribose) polymerase 1 (PARP1) for repair. Furthermore, nascent DNA at reprimed forks undergoes MRE11-dependent degradation, further destabilizing replication fork integrity. Consequently, LIPT1 deficiency promotes replication and genome instability, and therapeutic vulnerability to PARP inhibitor. Together, these findings reveal a mechanistic link between mitochondrial lipoylation and replication fork stability, uncovering a metabolic basis for genome instability in cancer.
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