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

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.

A new class of ultrafine anaphase bridges generated by homologous recombination

“…Several observations support the notion that HR-UFBs are distinct from all types of previously described UFBs [22,23]. First, in contrast to FS-UFBs, HR-UFBs do not associate with FANCD2 foci, a marker of late replication intermediates.…”

“…Interestingly, regions of sister chromatid bridging induced by 53BP1 depletion mapped close to a well-known fragile site (FRA16D in the WWOX locus) and to centromeres [23]. These results indicate that genomic loci that show high fragility and spontaneous breakage are likely to be repaired by HR in the absence of the anti-recombinogenic activity of 53BP1, leading to increased HR-mediated sister DNA intertwinements that are visualized as UFBs in anaphase.…”

“…Recently, two laboratories confirmed this notion and identified a new class of UFBs that are generated by homologous recombination [22,23]. In this article, we summarize and discuss how HR-UFBs are generated, which proteins are recruited, and their roles in bridge processing.…”

“…In parallel with these studies, work from another laboratory also described HR-generated UFBs that arose in 53BP1-depleted human cancer cells [23]. 53BP1 is regarded as a “gatekeeper” of DSB repair that plays a crucial role in determining DSB-repair pathway choice.…”

“…It is recruited to HR-UFBs in early anaphase when the two sister chromatids are just separating [22,23]. PICH is a member of the SNF2 family of DNA-dependent ATPases that possesses dsDNA translocase activity [5].…”