Cdc45 is limiting for replication initiation in humans
- Link:
- Autor/in:
- Erscheinungsjahr:
- 2016
- Medientyp:
- Text
- Schlagworte:
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- dk/atira/pure/publikationen_lom_relevant/cancer
- Cancer Medicine – University Cancer Center Hamburg (UCCH)
- Journal Article
- Research Support, Non-U.S. Gov't
- Beschreibung:
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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.
- Lizenz:
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- info:eu-repo/semantics/restrictedAccess
- Quellsystem:
- Forschungsinformationssystem des UKE
Interne Metadaten
- Quelldatensatz
- oai:pure.atira.dk:publications/d158f525-d9ce-4846-aea3-5e044fcfc7f6