53BP1 can limit sister-chromatid rupture and rearrangements driven by a distinct ultrafine DNA bridging-breakage process

Ankana Tiwari,Kok-Lung Chan,Owen Addis Jones

doi:10.1038/s41467-018-03098-y

Abstract

Chromosome missegregation acts as one of the driving forces for chromosome instability and cancer development. Here, we find that in human cancer cells, HeLa and U2OS, depletion of 53BP1 (p53-binding protein 1) exacerbates chromosome non-disjunction resulting from a new type of sister-chromatid intertwinement, which is distinct from FANCD2-associated ultrafine DNA bridges (UFBs) induced by replication stress. Importantly, the sister DNA intertwinements trigger gross chromosomal rearrangements through a distinct process, named sister-chromatid rupture and bridging. In contrast to conventional anaphase bridge-breakage models, we demonstrate that chromatid axes of the intertwined sister-chromatids rupture prior to the breakage of the DNA bridges. Consequently, the ruptured sister arms remain tethered and cause signature chromosome rearrangements, including whole-arm (Robertsonian-like) translocation/deletion and isochromosome formation. Therefore, our study reveals a hitherto unreported chromatid damage phenomenon mediated by sister DNA intertwinements that may help to explain the development of complex karyotypes in tumour cells.

Highlights

Chromosome missegregation acts as one of the driving forces for chromosome instability and cancer development
To gain insight into how cells prevent DNA entanglements arising during replication, we searched for proteins that co-localise with FANCD2 during unperturbed S phase
We found that 53BP1 forms spontaneous nuclear foci during DNA replication in both normal diploid and cancer cells (Supplementary Fig. 1a, b), where more than half of them surround the FANCD2 foci (Supplementary Fig. 1c, d)

Summary

Introduction

Chromosome missegregation acts as one of the driving forces for chromosome instability and cancer development. We find that in human cancer cells, HeLa and U2OS, depletion of 53BP1 (p53-binding protein 1) exacerbates chromosome non-disjunction resulting from a new type of sister-chromatid intertwinement, which is distinct from FANCD2-associated ultrafine DNA bridges (UFBs) induced by replication stress. A recent study has shown the association of replication stress and CIN20 It remains enigmatic how ultrafine DNA bridging structures may affect faithful chromosome segregation and genome stability. We have determined that human cancer cells (HeLa and U2OS) rely heavily on a non-homologous end-joining (NHEJ) factor 53BP121,22, for chromosome segregation, by limiting the formation of a new type of sister DNA intertwining structure that is not associated with FANCD2, but is dependent of RAD51. We reveal a new ultrafine DNA bridge-breakage process that drives gross chromosomal rearrangements in cultured human cancer cells, which is regulated by 53BP1

Methods

Results

Conclusion