A Distributed Architectural Code Governs DNA Repair
- 1University of Toronto
Abstract
Repair of DNA double-strand breaks (DSBs) depends on large-scale changes in nuclear shape and genome organization. How damage signaling coordinates such remodeling remains unclear. We find that the human DNA damage response (DDR) couples interdependent, temporally ordered tubulin modifications to nuclear membrane and lipid regulation, driving nuclear reshaping (nucleomorphosis) through DSB-capturing nuclear envelope tubules (dsbNETs). Tubulin detyrosination by vasohibins 1/2 (VASH1/2) and acetylation by -tubulin acetyltransferase 1 (ATAT1) promote dsbNET formation and support both homologous recombination and non-homologous end joining. Microtubule-dependent processes also promote the phosphorylation-dependent inactivation of the membrane stress-sensing lipid regulator CTP cytidylyltransferase- (CCT), which typically restrains baseline nuclear lipid droplets (nLDs) and dsbNETs while supporting ATR signaling. Damage-induced nLD formation requires diacylglycerol acyltransferases 1/2 (DGAT1/2) and supports dsbNETs. Our findings reveal a distributed architectural code spanning interconnected cytoskeletal, membrane, and lipid regulators. This code governs nucleomorphosis and its role in DNA repair and genome stability.
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BibTeX
@misc{hundal2026distributed,
title = {{A Distributed Architectural Code Governs DNA Repair}},
author = {A. Hundal and D. Urman and A. Algouneh and R. Krishnan and C. A. Jordan and S. Rudnizky and A. T. Rybczynski and T. Chkuaseli and A. Hakem and J. Hao and P. G. Maass and T. Ha and R. Hakem and K. Mekhail},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.759706},
url = {https://www.biorxiv.org/content/10.64898/2026.10.16.759706v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A Distributed Architectural Code Governs DNA Repair
AU - A. Hundal
AU - D. Urman
AU - A. Algouneh
AU - R. Krishnan
AU - C. A. Jordan
AU - S. Rudnizky
AU - A. T. Rybczynski
AU - T. Chkuaseli
AU - A. Hakem
AU - J. Hao
AU - P. G. Maass
AU - T. Ha
AU - R. Hakem
AU - K. Mekhail
PY - 2026
DA - 2026/10/16
PB - bioRxiv
DO - 10.64898/2026.10.16.759706
UR - https://www.biorxiv.org/content/10.64898/2026.10.16.759706v1
AB - Repair of DNA double-strand breaks (DSBs) depends on large-scale changes in nuclear shape and genome organization. How damage signaling coordinates such remodeling remains unclear. We find that the human DNA damage response (DDR) couples interdependent, temporally ordered tubulin modifications to nuclear membrane and lipid regulation, driving nuclear reshaping (nucleomorphosis) through DSB-capturing nuclear envelope tubules (dsbNETs). Tubulin detyrosination by vasohibins 1/2 (VASH1/2) and acetylation by -tubulin acetyltransferase 1 (ATAT1) promote dsbNET formation and support both homologous recombination and non-homologous end joining. Microtubule-dependent processes also promote the phosphorylation-dependent inactivation of the membrane stress-sensing lipid regulator CTP cytidylyltransferase- (CCT), which typically restrains baseline nuclear lipid droplets (nLDs) and dsbNETs while supporting ATR signaling. Damage-induced nLD formation requires diacylglycerol acyltransferases 1/2 (DGAT1/2) and supports dsbNETs. Our findings reveal a distributed architectural code spanning interconnected cytoskeletal, membrane, and lipid regulators. This code governs nucleomorphosis and its role in DNA repair and genome stability.
ER -