Journal
CELL CYCLE
Volume 15, Issue 7, Pages 974-985Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2016.1152424
Keywords
Apoptosis; CMG helicase; genome instability; origin firing; replication catastrophe; RPA; single-strand DNA
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Funding
- UFA Grant by the German Federal Office for Radiation Protection as part of the Kompetenzverbund fur Strahlenforschung [3610S30016]
- Federal Government of Germany
- State of Thuringia
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Cdc45 is an essential protein that together with Mcm2-7 and GINS forms the eukaryotic replicative helicase CMG. Cdc45 seems to be rate limiting for the initial unwinding or firing of replication origins. In line with this view, Cdc45-overexpressing cells fired at least twice as many origins as control cells. However, these cells displayed an about 2-fold diminished fork elongation rate, a pronounced asymmetry of replication fork extension, and an early S phase arrest. This was accompanied by H2AX-phosphorylation and subsequent apoptosis. Unexpectedly, we did not observe increased ATR/Chk1 signaling but rather a mild ATM/Chk2 response. In addition, we detected accumulation of long stretches of single-stranded DNA, a hallmark of replication catastrophe. We conclude that increased origin firing by upregulated Cdc45 caused exhaustion of the single-strand binding protein RPA, which in consequence diminished the ATR/Chk1 response; the subsequently occurring fork breaks led to an ATM/Chk2 mediated phosphorylation of H2AX and eventually to apoptosis.
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