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TONSL suppresses polymerase theta-dependent tandem duplications through chromatin-guided repair

Robin van Schendel1, Ron Romeijn1, Lejon E M Kralemann1,2

  • 1Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Nature Communications
|March 28, 2026
PubMed

Insights

The histone chaperone TONSL suppresses tandem duplications (TDs), common genomic rearrangements. Loss of TONSL leads to TD accumulation, highlighting its role in maintaining genome integrity across species.

Area of Science:

  • Genetics
  • Molecular Biology
  • Genomic Instability

Background:

  • Tandem duplications (TDs) are frequent genomic rearrangements with significant implications in cancer and evolution.
  • Despite their prevalence in cancer, TDs are seldom found in normal tissues, indicating active suppression mechanisms.
  • The mechanisms preventing TD formation in healthy cells remain largely unknown.

Purpose of the Study:

  • To identify key regulators that suppress tandem duplication formation.
  • To elucidate the molecular pathways involved in TD genesis and expansion.
  • To investigate the evolutionary conservation of TD suppression mechanisms.

Main Methods:

  • Utilized C. elegans (tnsl-1 mutant) and Arabidopsis thaliana models to study TD formation.
  • Employed molecular genetics techniques to assess TD accumulation and size.
  • Investigated the roles of polymerase theta-mediated end joining (TMEJ) and break-induced replication (BIR) in TD formation.

Main Results:

  • Identified the histone chaperone TONSL/TONSOKU as a critical suppressor of TD formation.
  • Demonstrated that loss of TONSL leads to the accumulation of two distinct size classes of TDs (~25 kb and ~300 kb).
  • Showed that TD formation depends on TMEJ and that BIR contributes to TD expansion.
  • Confirmed the conserved role of TONSL in suppressing TDs in both C. elegans and Arabidopsis thaliana.

Conclusions:

  • TONSL is an evolutionarily conserved guardian of genome integrity, acting as a key suppressor of tandem duplications.
  • TDs arise from DNA double-strand breaks and their expansion can be influenced by break-induced replication.
  • Understanding TONSL's function provides insights into preventing genomic instability in both normal and pathological conditions.

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