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bioRxiv · 10.1101/2021.12.09.471907

Nuclear NAD+ homeostasis is essential for naive and chemoresistant BRCA1/2-deficient tumor survival

Musiani, D.·Yucel, H.·Sourd, L.·Marangoni, E.·Ceccaldi, R.
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Abstract

Resistance to PARP inhibitors (PARPi) is emerging as the major obstacle to their effectiveness for the treatment of BRCA1/2-mutated, also referred as homologous recombination (HR)-deficient, tumors (HRD). Over the years, mechanistic studies gained insights on effectors acting downstream of PARP1, lagging behind the understanding of earlier events upstream - and thus independent - of PARP1. Here, we investigated the role of nuclear NAD+, an essential cofactor for the activity of key DNA repair proteins, including PARP1 and sirtuins. We show that NMNAT1-the enzyme synthesizing nuclear NAD+ - is synthetically lethal with BRCA1/2 in a PARP1-independent but SIRT6-dependent manner. Consequently, inhibition of NMNAT1/SIRT6 axis not only kills naive but also PARPi-resistant HRD cancer cells. Our results unravel a unique vulnerability of HRD tumors, therapeutically exploitable even upon PARPi resistance development. One-Sentence SummaryTargeting NMNAT1 kills chemoresistant and naive BRCA1/2-deficient tumors by disrupting SIRT6-dependent base excision repair.

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Musiani, D., Yucel, H., Sourd, L., Marangoni, E., Ceccaldi, R.. 2021-12-09. Nuclear NAD+ homeostasis is essential for naive and chemoresistant BRCA1/2-deficient tumor survival. https://doi.org/10.1101/2021.12.09.471907

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