THE NSL COMPLEX PROMOTES NEURAL DEVELOPMENT BY PREVENTING R-LOOP INDUCED REPLICATION STRESS

Jolanthe Lingeman; Diana van den Heuvel; Jeroen van den Berg; Jenny Kaur Singh; Rosanne van Hooijdonk; Wouter W. Wiegant; Daphne E.C. Boer; Calvin Shun Yu Lo; Ανδρέας Παναγόπουλος; Román González‐Prieto; Marnix Franken; Nikki Kolsters; Olivier G. de Jong; Alfred C.O. Vertegaal; Matthias Altmeyer; Nitika Taneja; Alexander van Oudenaarden; Martijn S. Luijsterburg; Nael Nadif Kasri; Brooke L. Latour; Haico van Attikum

doi:10.1101/2025.08.22.671281

GenomicsbioRxivAug 22, 2025

Preprint

THE NSL COMPLEX PROMOTES NEURAL DEVELOPMENT BY PREVENTING R-LOOP INDUCED REPLICATION STRESS

Jolanthe Lingeman iD, Diana van den Heuvel iD, Jeroen van den Berg iD, Jenny Kaur Singh iD, Rosanne van Hooijdonk, Wouter W. Wiegant iD, Daphne E.C. Boer iD, Calvin Shun Yu Lo iD, Ανδρέας Παναγόπουλος iD, Román González‐Prieto iD, Marnix Franken iD, Nikki Kolsters iD, Olivier G. de Jong iD, Alfred C.O. Vertegaal iD, Matthias Altmeyer iD, Nitika Taneja iD, Alexander van Oudenaarden iD, Martijn S. Luijsterburg iD, Nael Nadif Kasri iD, Brooke L. Latour iD, Haico van Attikum iD

Abstract

Early neuronal development relies on the proliferation of neural progenitor cells, making this developmental stage particularly vulnerable to DNA replication impediments. Here, we identify a non-canonical role for the non-specific lethal (NSL) complex in safeguarding DNA replication during neurodevelopment. The NSL complex, which acetylates histone 4 at gene promoters and is mutated in Koolen-de Vries syndrome (KdVS), prevents unscheduled R-loop accumulation at weakly transcribed promoters that are typically devoid of R-loops. Single-cell sequencing reveals that loss of NSL causes replisome stalling and delayed S-phase progression. Neural organoids derived from KdVS patients exhibit impaired DNA replication, developmental abnormalities, and reduced synapse formation, driven entirely by unscheduled R-loop accumulation. These findings reveal that faithful DNA replication is critical for early neurodevelopment.

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