PT  - JOURNAL ARTICLE
AU  - John Maciejowski
AU  - Aikaterini Chatzipli
AU  - Alexandra Dananberg
AU  - Titia de Lange
AU  - Peter J. Campbell
TI  - APOBEC3B-dependent kataegis and TREX1-driven chromothripsis in telomere crisis
AID  - 10.1101/725366
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 725366
4099  - http://biorxiv.org/content/early/2019/08/05/725366.short
4100  - http://biorxiv.org/content/early/2019/08/05/725366.full
AB  - Chromothripsis and kataegis are frequently observed in cancer and can arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes1–5. Here we report on the mechanism underlying chromothripsis and kataegis using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes4, plays a prominent role in chromothriptic fragmentation. In absence of TREX1, the genome alterations induced by telomere crisis primarily involve Breakage-Fusion-Bridge cycles and simple genome rearrangements rather than chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. In addition, APOBEC3B increased the frequency of chromothriptic fragmentation, possibly due to strand breakage after cytosine deamination. These data reveal that chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.