Trans-branching of polyubiquitin chains orchestrates the DNA replication stress response
- 1Institute of Molecular Biology gGmbH (IMB)
Abstract
Polyubiquitin chain geometry dictates functional consequences of ubiquitylation. Although branched polyubiquitin chains are abundant in cells, little is known about their functions. Here we show that branching on the DNA replication factor PCNA, mediated by the ubiquitin-conjugating enzyme UBE2K and involving lysines 63 and 48 of ubiquitin, orchestrates the sequence of events in response to replication stress. By inducing VCP-dependent extraction of PCNA from chromatin, branching promotes re-priming of stalled forks and necessitates a BRCA1-dependent pathway of daughter-strand gap repair. Our study identifies hyper-accumulation of daughter-strand gaps as the mechanistic basis underlying the toxicity of inhibitors of the PCNA-specific isopeptidase, USP1, in BRCA1-deficient cells. Moreover, an unexpected preference of UBE2K to operate in trans suggests a general timing mechanism to organize hierarchies amongst ubiquitin signals.
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BibTeX
@misc{petriukov2026transbranching,
title = {{Trans-branching of polyubiquitin chains orchestrates the DNA replication stress response}},
author = {K. Petriukov and C. Renz and M. S. Schraft and I. Mikicic and N. C. Krapoth and A. Thapa and P. Beli and H. D. Ulrich},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748521},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748521v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Trans-branching of polyubiquitin chains orchestrates the DNA replication stress response
AU - K. Petriukov
AU - C. Renz
AU - M. S. Schraft
AU - I. Mikicic
AU - N. C. Krapoth
AU - A. Thapa
AU - P. Beli
AU - H. D. Ulrich
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748521
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748521v1
AB - Polyubiquitin chain geometry dictates functional consequences of ubiquitylation. Although branched polyubiquitin chains are abundant in cells, little is known about their functions. Here we show that branching on the DNA replication factor PCNA, mediated by the ubiquitin-conjugating enzyme UBE2K and involving lysines 63 and 48 of ubiquitin, orchestrates the sequence of events in response to replication stress. By inducing VCP-dependent extraction of PCNA from chromatin, branching promotes re-priming of stalled forks and necessitates a BRCA1-dependent pathway of daughter-strand gap repair. Our study identifies hyper-accumulation of daughter-strand gaps as the mechanistic basis underlying the toxicity of inhibitors of the PCNA-specific isopeptidase, USP1, in BRCA1-deficient cells. Moreover, an unexpected preference of UBE2K to operate in trans suggests a general timing mechanism to organize hierarchies amongst ubiquitin signals.
ER -