S phase block following MEC1(ATR) inactivation occurs without severe dNTP depletion

Earp, C. and Rowbotham, S. and Merenyi, G. and Chabes, A. and Cha, R.S. (2015) S phase block following MEC1(ATR) inactivation occurs without severe dNTP depletion. Biology Open, 4 (12). pp. 1739-1743. DOI: 10.1242/bio.015347

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Inactivation of Mec1, the budding yeast ATR, results in a permanent S phase arrest followed by chromosome breakage and cell death during G2/M. The S phase arrest is proposed to stem from a defect in Mec1-mediated degradation of Sml1, a conserved inhibitor of ribonucleotide reductase (RNR), causing a severe depletion in cellular dNTP pools. Here, the casual link between the S phase arrest, Sml1, and dNTP-levels is examined using a temperature sensitive mec1 mutant. In addition to S phase arrest, thermal inactivation of Mec1 leads to constitutively high levels of Sml1 and an S phase arrest. Expression of a novel suppressor, GIS2, a conserved mRNA binding zinc finger protein, rescues the arrest without down-regulating Sml1 levels. The dNTP pool in mec1 is reduced by �17% and GIS2 expression restores it, but only partially, to �93% of a control. We infer that the permanent S phase block following Mec1 inactivation can be uncoupled from its role in Sml1 down-regulation. Furthermore, unexpectedly modest effects of mec1 and GIS2 on dNTP levels suggest that the S phase arrest is unlikely to result from a severe depletion of dNTP pool as assumed, but a heightened sensitivity to small changes in its availability.

Item Type: Article
Subjects: Research Publications
Departments: College of Health and Behavioural Sciences > School of Medical Sciences
Date Deposited: 18 Feb 2016 03:12
Last Modified: 18 Feb 2016 03:12
ISSN: 2046-6390
URI: http://e.bangor.ac.uk/id/eprint/6251
Identification Number: DOI: 10.1242/bio.015347
Publisher: Company of Biologists
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