DNA replication in early S phase pauses near newly activated origins.

Cell Cycle
Rebecca A FrumDavid G Kaufman

Abstract

During the S phase of the cell cycle, the entire genome is replicated. There is a high level of orderliness to this process through the temporally and topologically coordinated activation of many replication origins situated along chromosomes. We investigated the program of replication from origins initiating in early S phase by labeling synchronized normal human fibroblasts (NHF1) with nucleotide analogs for various pulse times and measuring labeled tracks in combed DNA fibers. Our analysis showed that replication forks progress 9-35 kilobases from newly initiated origins, followed by a pause in synthesis before replication resumes. Pausing was not observed near origins that initiated in the middle of S phase. No evidence for pausing near origins was found at the beginning of the S phase in glioblastoma T98G cells. Treatment with the S phase checkpoint inhibitor caffeine abrogated pausing in NHF1 cells in early S phase. This suggests that pausing may comprise a novel aspect of the intra-S phase checkpoint pathway or a related new early S checkpoint. Further, it is possible that the loss of this regulatory process in cancer cells such as T98G could be a contributing factor in the genetic instability that typifies cancers.

Citations

Jan 1, 2009·Genome Biology and Evolution·Sara C Di RienziBonita J Brewer
Jun 1, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Paul D ChastainDavid G Kaufman
May 16, 2009·Epigenetics & Chromatin·Stephanie M CohenDavid G Kaufman
Jan 11, 2011·The Journal of Steroid Biochemistry and Molecular Biology·Zhong-Wei XuRui-Cheng Xu
Nov 26, 2010·Advances in Enzyme Regulation·David G KaufmanPaul D Chastain
Dec 3, 2011·Journal of Cellular Biochemistry·Domenic Di Paola, Maria Zannis-Hadjopoulos
Oct 16, 2014·Photochemistry and Photobiology·Paul D ChastainMarila Cordeiro-Stone
Apr 11, 2017·The Journal of Clinical Investigation·Shilpa SinghSwati Palit Deb

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