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Break-induced replication promotes fragile telomere formation.

Zhe Yang1, Kaori K Takai1, Courtney A Lovejoy1

  • 1Laboratory for Cell Biology and Genetics, Rockefeller University; New York 10021, USA.

Genes & Development
|September 5, 2020
PubMed
Summary

Fragile telomeres arise from DNA double-strand breaks repaired by break-induced replication (BIR), not alternative nonhomologous end joining. This mechanism explains telomere fragility in various cellular contexts.

Keywords:
BLMG4POLD3POLD4SLX1SLX4TRF1break-induced replicationfragile telomeretelomere

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Area of Science:

  • Genetics
  • Molecular Biology
  • Cell Biology

Background:

  • Telomere replication relies on TRF1 and BLM helicase to resolve G-quadruplexes.
  • Deficiency in TRF1 or BLM leads to fragile telomeres, similar to common fragile sites (CFSs), but the mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism behind fragile telomere formation in BLM-deficient cells.
  • To investigate the role of DNA repair pathways in telomere fragility.

Main Methods:

  • Analysis of BLM-deficient cells and cells with induced telomeric double-strand breaks (DSBs).
  • Investigated the involvement of SLX4/SLX1 nuclease in DSB formation.
  • Studied the repair of DSBs via POLD3/POLD4-dependent break-induced replication (BIR).
  • Compared BIR with PARP1-, LIG3-, and XPF-dependent alternative nonhomologous end joining (alt-NHEJ).

Main Results:

  • Fragile telomeres in BLM-deficient cells involve SLX4/SLX1-mediated DSBs repaired by BIR.
  • BIR results in conservatively replicated DNA within fragile telomeres.
  • BIR promotes fragile telomere formation in cells with induced telomeric DSBs and in ALT cells.
  • BIR competes with alt-NHEJ, which does not generate fragile telomeres.

Conclusions:

  • Fragile telomeres can form through the BIR repair of telomeric DSBs.
  • This mechanism is relevant in cells lacking BLM, with induced telomeric damage, and in ALT cells.
  • The balance between BIR and alt-NHEJ influences telomere fragility.