Genome-wide profiling of DNA repair proteins in single cells

Kim L. Luca (), Pim M. J. Rullens, Magdalena A. Karpinska, Sandra S. Vries, Agnieszka Gacek-Matthews, Lőrinc S. Pongor, Gaëlle Legube, Joanna W. Jachowicz, A. Marieke Oudelaar and Jop Kind ()
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Kim L. Luca: Royal Netherlands Academy of Arts and Sciences (KNAW) & University Medical Center Utrecht
Pim M. J. Rullens: Royal Netherlands Academy of Arts and Sciences (KNAW) & University Medical Center Utrecht
Magdalena A. Karpinska: Max Planck Institute for Multidisciplinary Sciences
Sandra S. Vries: Royal Netherlands Academy of Arts and Sciences (KNAW) & University Medical Center Utrecht
Agnieszka Gacek-Matthews: Vienna Biocenter (VBC)
Lőrinc S. Pongor: Hungarian Center of Excellence for Molecular Medicine (HCEMM)
Gaëlle Legube: Université de Toulouse
Joanna W. Jachowicz: Vienna Biocenter (VBC)
A. Marieke Oudelaar: Max Planck Institute for Multidisciplinary Sciences
Jop Kind: Royal Netherlands Academy of Arts and Sciences (KNAW) & University Medical Center Utrecht

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Accurate repair of DNA damage is critical for maintenance of genomic integrity and cellular viability. Because damage occurs non-uniformly across the genome, single-cell resolution is required for proper interrogation, but sensitive detection has remained challenging. Here, we present a comprehensive analysis of repair protein localization in single human cells using DamID and ChIC sequencing techniques. This study reports genome-wide binding profiles in response to DNA double-strand breaks induced by AsiSI, and explores variability in genomic damage locations and associated repair features in the context of spatial genome organization. By unbiasedly detecting repair factor localization, we find that repair proteins often occupy entire topologically associating domains, mimicking variability in chromatin loop anchoring. Moreover, we demonstrate the formation of multi-way chromatin hubs in response to DNA damage. Notably, larger hubs show increased coordination of repair protein binding, suggesting a preference for cooperative repair mechanisms. Together, our work offers insights into the heterogeneous processes underlying genome stability in single cells.

Date: 2024
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DOI: 10.1038/s41467-024-54159-4

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