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Cdc45 is limiting for replication initiation in humans

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Cdc45 is limiting for replication initiation in humans. / Köhler, Carsten; Koalick, Dennis; Fabricius, Anja; Parplys, Ann Christin; Borgmann, Kerstin; Pospiech, Helmut; Grosse, Frank.

In: CELL CYCLE, Vol. 15, No. 7, 2016, p. 974-85.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Köhler, C, Koalick, D, Fabricius, A, Parplys, AC, Borgmann, K, Pospiech, H & Grosse, F 2016, 'Cdc45 is limiting for replication initiation in humans', CELL CYCLE, vol. 15, no. 7, pp. 974-85. https://doi.org/10.1080/15384101.2016.1152424

APA

Köhler, C., Koalick, D., Fabricius, A., Parplys, A. C., Borgmann, K., Pospiech, H., & Grosse, F. (2016). Cdc45 is limiting for replication initiation in humans. CELL CYCLE, 15(7), 974-85. https://doi.org/10.1080/15384101.2016.1152424

Vancouver

Köhler C, Koalick D, Fabricius A, Parplys AC, Borgmann K, Pospiech H et al. Cdc45 is limiting for replication initiation in humans. CELL CYCLE. 2016;15(7):974-85. https://doi.org/10.1080/15384101.2016.1152424

Bibtex

@article{d158f525d9ce4846aea35e044fcfc7f6,
title = "Cdc45 is limiting for replication initiation in humans",
abstract = "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.",
keywords = "Journal Article, Research Support, Non-U.S. Gov't",
author = "Carsten K{\"o}hler and Dennis Koalick and Anja Fabricius and Parplys, {Ann Christin} and Kerstin Borgmann and Helmut Pospiech and Frank Grosse",
year = "2016",
doi = "10.1080/15384101.2016.1152424",
language = "English",
volume = "15",
pages = "974--85",
journal = "CELL CYCLE",
issn = "1538-4101",
publisher = "LANDES BIOSCIENCE",
number = "7",

}

RIS

TY - JOUR

T1 - Cdc45 is limiting for replication initiation in humans

AU - Köhler, Carsten

AU - Koalick, Dennis

AU - Fabricius, Anja

AU - Parplys, Ann Christin

AU - Borgmann, Kerstin

AU - Pospiech, Helmut

AU - Grosse, Frank

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1080/15384101.2016.1152424

DO - 10.1080/15384101.2016.1152424

M3 - SCORING: Journal article

C2 - 26919204

VL - 15

SP - 974

EP - 985

JO - CELL CYCLE

JF - CELL CYCLE

SN - 1538-4101

IS - 7

ER -