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| Status |
Public on Dec 31, 2022 |
| Title |
Tight CDK1 inhibition elicits domain-specific pre-RC setting in S-phase, suppressing CFS instability |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
Genome integrity requires replication to be completed before chromosome segregation. This coordination essentially relies on replication-dependent activation of a dedicated checkpoint that inhibits CDK1, delaying mitotic onset. Under-replication of Common Fragile Sites (CFSs), however, escapes surveillance, which generates mitotic chromosome breaks. Using human cells, we asked whether this leakage results from insufficient CDK1 inhibition under modest stresses used to destabilize CFSs. We found that tight CDK1 inhibition does suppress CFS instability in so-stressed cells. Molecular combing and Repli-Seq analyses consistently showed a burst of replication initiations in mid S-phase across large origin-poor domains shaped by transcription, including CFSs. CFS rescue and extra-initiations strikingly require availability of essential pre-Replication Complex (pre-RC) proteins during the S-phase, showing that CDK1 inhibition promotes targeted and mistimed pre-RC reloading. In addition to delay mitotic onset, tight checkpoint activation therefore advances replication completion of origin-poor domains at risk of under-replication, two complementary roles preserving genome stability.
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| Overall design |
Repli-Seq experiments of human lymphoblastoid cells grown in the following conditions: Normal media (1 sample), 600 nM aphidicolin for 16h (1 sample), 600 nM aphidicolin and 10μM CDK1 inhibitor for 16h (two samples), 150μM HU for 16h (1 sample) and 150μM HU and 100mM Atr inhibitor for 16h.
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| Contributor(s) |
Chen C, Gnan S, Brison O, Azar D, Koundrioukoff S, Schmidt M, Meledez-Garcia R, El-Hilali S, Jaszczyszyn Y, Lachages A, Thermes C, Debatisse M |
| Citation(s) |
37024657 |
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| Submission date |
Oct 04, 2021 |
| Last update date |
Jul 31, 2023 |
| Contact name |
Chunlong Chen |
| E-mail(s) |
chunlong.chen@curie.fr
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| Organization name |
Institut Curie
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| Department |
UMR3244
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| Street address |
26 rue d’Ulm
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| City |
Paris |
| ZIP/Postal code |
75005 |
| Country |
France |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (30)
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| Relations |
| BioProject |
PRJNA768449 |
| SRA |
SRP339971 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE185282_Average_profile_ARO_G1-S1.BigWig |
24.6 Mb |
(ftp)(http) |
BIGWIG |
| GSE185282_Average_profile_ARO_S2.BigWig |
25.2 Mb |
(ftp)(http) |
BIGWIG |
| GSE185282_Average_profile_ARO_S3.BigWig |
25.3 Mb |
(ftp)(http) |
BIGWIG |
| GSE185282_Average_profile_ARO_S4.BigWig |
25.1 Mb |
(ftp)(http) |
BIGWIG |
| GSE185282_Average_profile_ARO_S5.BigWig |
24.5 Mb |
(ftp)(http) |
BIGWIG |
| GSE185282_Average_profile_ARO_S6-G2-M.BigWig |
24.4 Mb |
(ftp)(http) |
BIGWIG |
| GSE185282_RAW.tar |
429.6 Mb |
(http)(custom) |
TAR (of BIGWIG) |
| GSE185282_S50_NT.BigWig |
22.9 Mb |
(ftp)(http) |
BIGWIG |
| GSE185282_URI_ARO.BigWig |
26.4 Mb |
(ftp)(http) |
BIGWIG |
| GSE185282_URI_HU+ATRi.BigWig |
26.3 Mb |
(ftp)(http) |
BIGWIG |
| GSE185282_URI_HU.BigWig |
26.3 Mb |
(ftp)(http) |
BIGWIG |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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