scholarly journals Rapid DNA Replication Origin Licensing Protects Stem Cell Pluripotency

2017 ◽  
Author(s):  
Jacob Peter Matson ◽  
Raluca Dumitru ◽  
Phillip Coryell ◽  
Ryan M Baxley ◽  
Weili Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Replication ◽  
Cell Types ◽  
Origin Licensing ◽  
Mcm Helicase ◽  
Dna Replication Origin ◽  
Stem Cell Pluripotency ◽  
Dna Replication Origins ◽  
Pluripotency Maintenance ◽  
Intrinsic Characteristic

ABSTRACTComplete and robust human genome duplication requires loading MCM helicase complexes at many DNA replication origins, an essential process termed origin licensing. Licensing is restricted to G1 phase of the cell cycle, but G1 length varies widely among cell types. Using quantitative single cell analyses we found that pluripotent stem cells with naturally short G1 phases load MCM much faster than their isogenic differentiated counterparts with long G1 phases. During the earliest stages of differentiation towards all lineages, MCM loading slows concurrently with G1 lengthening, revealing developmental control of MCM loading. In contrast, ectopic Cyclin E overproduction uncouples short G1 from fast MCM loading. Rapid licensing in stem cells is caused by accumulation of the MCM loading protein, Cdt1. Prematurely slowing MCM loading in pluripotent cells not only lengthens G1 but also accelerates differentiation. Thus, rapid origin licensing is an intrinsic characteristic of stem cells that contributes to pluripotency maintenance.

scholarly journals Rapid DNA replication origin licensing protects stem cell pluripotency

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jacob Peter Matson ◽  
Raluca Dumitru ◽  
Philip Coryell ◽  
Ryan M Baxley ◽  
Weili Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Replication ◽  
Cell Types ◽  
Minichromosome Maintenance ◽  
Origin Licensing ◽  
Mcm Helicase ◽  
Dna Replication Origin ◽  
Stem Cell Pluripotency ◽  
Dna Replication Origins ◽  
Intrinsic Characteristic

Complete and robust human genome duplication requires loading minichromosome maintenance (MCM) helicase complexes at many DNA replication origins, an essential process termed origin licensing. Licensing is restricted to G1 phase of the cell cycle, but G1 length varies widely among cell types. Using quantitative single-cell analyses, we found that pluripotent stem cells with naturally short G1 phases load MCM much faster than their isogenic differentiated counterparts with long G1 phases. During the earliest stages of differentiation toward all lineages, MCM loading slows concurrently with G1 lengthening, revealing developmental control of MCM loading. In contrast, ectopic Cyclin E overproduction uncouples short G1 from fast MCM loading. Rapid licensing in stem cells is caused by accumulation of the MCM loading protein, Cdt1. Prematurely slowing MCM loading in pluripotent cells not only lengthens G1 but also accelerates differentiation. Thus, rapid origin licensing is an intrinsic characteristic of stem cells that contributes to pluripotency maintenance.

scholarly journals Author response: Rapid DNA replication origin licensing protects stem cell pluripotency

2017 ◽  
Author(s):  
Jacob Peter Matson ◽  
Raluca Dumitru ◽  
Philip Coryell ◽  
Ryan M Baxley ◽  
Weili Chen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Dna Replication ◽  
Replication Origin ◽  
Author Response ◽  
Origin Licensing ◽  
Dna Replication Origin ◽  
Stem Cell Pluripotency

scholarly journals Correction: Rapid DNA replication origin licensing protects stem cell pluripotency

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jacob Peter Matson ◽  
Raluca Dumitru ◽  
Philip Coryell ◽  
Ryan M Baxley ◽  
Weili Chen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Dna Replication ◽  
Replication Origin ◽  
Origin Licensing ◽  
Dna Replication Origin ◽  
Stem Cell Pluripotency

scholarly journals Intrinsic checkpoint deficiency during cell cycle re-entry from quiescence

2019 ◽  
Author(s):  
Jacob Peter Matson ◽  
Amy M. House ◽  
Gavin D. Grant ◽  
Huaitong Wu ◽  
Joanna Perez ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Genome Instability ◽  
Replication Stress ◽  
S Phase ◽  
Minichromosome Maintenance ◽  
Cell Cycle Entry ◽  
Origin Licensing ◽  
Dna Replication Origin ◽  
Dna Replication Origins

SUMMARYThe authors find that human cells re-entering the cell cycle from quiescence have both an impaired p53-dependent DNA replication origin licensing checkpoint and slow origin licensing. This combination makes every first S phase underlicensed and hypersensitive to replication stress.ABSTRACTTo maintain tissue homeostasis, cells transition between cell cycle quiescence and proliferation. An essential G1 process is Minichromosome Maintenance complex (MCM) loading at DNA replication origins to prepare for S phase, known as origin licensing. A p53-dependent origin licensing checkpoint normally ensures sufficient MCM loading prior to S phase entry. We used quantitative flow cytometry and live cell imaging to compare MCM loading during the long first G1 upon cell cycle entry and the shorter G1 phases in the second and subsequent cycles. We discovered that despite the longer G1 phase, the first G1 after cell cycle re-entry is significantly underlicensed. As a result, the first S phase cells are hypersensitive to replication stress. This underlicensing is from a combination of slow MCM loading with a severely compromised origin licensing checkpoint. The hypersensitivity to replication stress increases over repeated rounds of quiescence. Thus, underlicensing after cell cycle re-entry from quiescence distinguishes a higher risk cell cycle that promotes genome instability.

scholarly journals Concerted Loading of Mcm2–7 Double Hexamers around DNA during DNA Replication Origin Licensing

Cell ◽  
2009 ◽  
Vol 139 (4) ◽  
pp. 719-730 ◽  
Author(s):  
Dirk Remus ◽  
Fabienne Beuron ◽  
Gökhan Tolun ◽  
Jack D. Griffith ◽  
Edward P. Morris ◽  
...  
Keyword(s):  
Dna Replication ◽  
Replication Origin ◽  
Origin Licensing ◽  
Dna Replication Origin
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