Abstract
DNA replication in eukaryotic cells is tightly controlled by a licensing mechanism, ensuring that each origin fires once and only once per cell cycle. We demonstrate that the ataxia telangiectasia and Rad3 related (ATR)-mediated S phase checkpoint acts as a surveillance mechanism to prevent rereplication. Thus, disruption of licensing control will not induce significant rereplication in mammalian cells when the ATR checkpoint is intact. We also demonstrate that single-stranded DNA (ssDNA) is the initial signal that activates the checkpoint when licensing control is compromised in mammalian cells. We demonstrate that uncontrolled DNA unwinding by minichromosome maintenance proteins upon Cdt1 overexpression is an important mechanism that leads to ssDNA accumulation and checkpoint activation. Furthermore, we show that replication protein A 2 and retinoblastoma protein are both downstream targets for ATR that are important for the inhibition of DNA rereplication. We reveal the molecular mechanisms by which the ATR-mediated S phase checkpoint pathway prevents DNA rereplication and thus significantly improve our understanding of how rereplication is prevented in mammalian cells.
| Original language | English |
|---|---|
| Pages (from-to) | 643-657 |
| Number of pages | 15 |
| Journal | Journal of Cell Biology |
| Volume | 179 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2007 Nov 19 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cell Biology
Cite this
The ATR-mediated S phase checkpoint prevents rereplication in mammalian cells when licensing control is disrupted. / Liu, Enbo; Lee, Alan Yueh Luen; Chiba, Takuya; Olson, Erin; Sun, Peiqing; Wu, Xiaohua.
In: Journal of Cell Biology, Vol. 179, No. 4, 19.11.2007, p. 643-657.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The ATR-mediated S phase checkpoint prevents rereplication in mammalian cells when licensing control is disrupted
AU - Liu, Enbo
AU - Lee, Alan Yueh Luen
AU - Chiba, Takuya
AU - Olson, Erin
AU - Sun, Peiqing
AU - Wu, Xiaohua
PY - 2007/11/19
Y1 - 2007/11/19
N2 - DNA replication in eukaryotic cells is tightly controlled by a licensing mechanism, ensuring that each origin fires once and only once per cell cycle. We demonstrate that the ataxia telangiectasia and Rad3 related (ATR)-mediated S phase checkpoint acts as a surveillance mechanism to prevent rereplication. Thus, disruption of licensing control will not induce significant rereplication in mammalian cells when the ATR checkpoint is intact. We also demonstrate that single-stranded DNA (ssDNA) is the initial signal that activates the checkpoint when licensing control is compromised in mammalian cells. We demonstrate that uncontrolled DNA unwinding by minichromosome maintenance proteins upon Cdt1 overexpression is an important mechanism that leads to ssDNA accumulation and checkpoint activation. Furthermore, we show that replication protein A 2 and retinoblastoma protein are both downstream targets for ATR that are important for the inhibition of DNA rereplication. We reveal the molecular mechanisms by which the ATR-mediated S phase checkpoint pathway prevents DNA rereplication and thus significantly improve our understanding of how rereplication is prevented in mammalian cells.
AB - DNA replication in eukaryotic cells is tightly controlled by a licensing mechanism, ensuring that each origin fires once and only once per cell cycle. We demonstrate that the ataxia telangiectasia and Rad3 related (ATR)-mediated S phase checkpoint acts as a surveillance mechanism to prevent rereplication. Thus, disruption of licensing control will not induce significant rereplication in mammalian cells when the ATR checkpoint is intact. We also demonstrate that single-stranded DNA (ssDNA) is the initial signal that activates the checkpoint when licensing control is compromised in mammalian cells. We demonstrate that uncontrolled DNA unwinding by minichromosome maintenance proteins upon Cdt1 overexpression is an important mechanism that leads to ssDNA accumulation and checkpoint activation. Furthermore, we show that replication protein A 2 and retinoblastoma protein are both downstream targets for ATR that are important for the inhibition of DNA rereplication. We reveal the molecular mechanisms by which the ATR-mediated S phase checkpoint pathway prevents DNA rereplication and thus significantly improve our understanding of how rereplication is prevented in mammalian cells.
UR - http://www.scopus.com/inward/record.url?scp=36348931639&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36348931639&partnerID=8YFLogxK
U2 - 10.1083/jcb.200704138
DO - 10.1083/jcb.200704138
M3 - Article
C2 - 18025301
AN - SCOPUS:36348931639
VL - 179
SP - 643
EP - 657
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 4
ER -