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Checkpoint Kinase Rad53 Couples Leading- and Lagging-Strand DNA Synthesis under Replication Stress
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. (Andrei Chabes)
Vise andre og tillknytning
2017 (engelsk)Inngår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 68, nr 2, s. 446-455Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The checkpoint kinase Rad53 is activated during replication stress to prevent fork collapse, an essential but poorly understood process. Here we show that Rad53 couples leading- and lagging-strand synthesis under replication stress. In rad53-1 cells stressed by dNTP depletion, the replicative DNA helicase, MCM, and the leading-strand DNA polymerase, Pol ε, move beyond the site of DNA synthesis, likely unwinding template DNA. Remarkably, DNA synthesis progresses further along the lagging strand than the leading strand, resulting in the exposure of long stretches of single-stranded leading-strand template. The asymmetric DNA synthesis in rad53-1 cells is suppressed by elevated levels of dNTPs in vivo, and the activity of Pol ε is compromised more than lagging-strand polymerase Pol δ at low dNTP concentrations in vitro. Therefore, we propose that Rad53 prevents the generation of excessive ssDNA under replication stress by coordinating DNA unwinding with synthesis of both strands.

sted, utgiver, år, opplag, sider
Elsevier, 2017. Vol. 68, nr 2, s. 446-455
Emneord [en]
ChIP-ssSeq, DNA replication checkpoint, Rad53, dNTP pools, eSPAN, fork collapse, lagging strand DNA synthesis, leading strand DNA synthesis
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Identifikatorer
URN: urn:nbn:se:umu:diva-140697DOI: 10.1016/j.molcel.2017.09.018ISI: 000413239400017PubMedID: 29033319OAI: oai:DiVA.org:umu-140697DiVA, id: diva2:1149943
Tilgjengelig fra: 2017-10-17 Laget: 2017-10-17 Sist oppdatert: 2018-06-09bibliografisk kontrollert

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