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Separable roles for Mec1/ATR in genome maintenance, DNA replication, and checkpoint signaling
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). (Andrei Chabes)
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2018 (English)In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 32, no 11-12, p. 822-835Article in journal (Refereed) Published
Abstract [en]

The Mec1/ATR kinase coordinates multiple cellular responses to replication stress. In addition to its canonical role in activating the checkpoint kinase Rad53, Mec1 also plays checkpoint-independent roles in genome maintenance that are not well understood. Here we used a combined genetic-phosphoproteomic approach to manipulate Mec1 activation and globally monitor Mec1 signaling, allowing us to delineate distinct checkpoint-independent modes of Mec1 action. Using cells in which endogenous Mec1 activators were genetically ablated, we found that expression of "free" Mec1 activation domains (MADs) can robustly activate Mec1 and rescue the severe DNA replication and growth defects of these cells back to wild-type levels. However, unlike the activation mediated by endogenous activator proteins, "free" MADs are unable to stimulate Mec1-mediated suppression of gross chromosomal rearrangements (GCRs), revealing that Mec1's role in genome maintenance is separable from a previously unappreciated proreplicative function. Both Mec1's functions in promoting replication and suppressing GCRs are independent of the downstream checkpoint kinases. Additionally, Mec1-dependent GCR suppression seems to require localized Mec1 action at DNA lesions, which correlates with the phosphorylation of activator-proximal substrates involved in homologous recombination-mediated DNA repair. These findings establish that Mec1 initiates checkpoint signaling, promotes DNA replication, and maintains genetic stability through distinct modes of action.

Place, publisher, year, edition, pages
2018. Vol. 32, no 11-12, p. 822-835
Keywords [en]
ATR, DNA replication, Dna2, Dpb11, Mec1, gross chromosomal rearrangements
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-150961DOI: 10.1101/gad.308148.117ISI: 000436070000008PubMedID: 29899143Scopus ID: 2-s2.0-85048778293OAI: oai:DiVA.org:umu-150961DiVA, id: diva2:1240363
Available from: 2018-08-21 Created: 2018-08-21 Last updated: 2018-08-31Bibliographically approved

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Sharma, SushmaChabes, Andrei
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