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Conserved forkhead dimerization motif controls DNA replication timing and spatial organization of chromosomes inS. cerevisiae

Ostrow, A. Zachary, Kalhor, Reza, Gan, Yan, Villwock, Sandra K., Linke, Christian, Barberis, Matteo, Chen, Lin and Aparicio, Oscar M. (2017) Conserved forkhead dimerization motif controls DNA replication timing and spatial organization of chromosomes inS. cerevisiae PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 114 (12). E2411-E2419.

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Forkhead Box (Fox) proteins share the Forkhead domain, a wingedhelix DNA binding module, which is conserved among eukaryotes from yeast to humans. These sequence-specific DNA binding proteins have been primarily characterized as transcription factors regulating diverse cellular processes from cell cycle control to developmental fate, deregulation of which contributes to developmental defects, cancer, and aging. We recently identified Saccharomyces cerevisiae Forkhead 1 (Fkh1) and Forkhead 2 (Fkh2) as required for the clustering of a subset of replication origins in G1 phase and for the early initiation of these origins in the ensuing S phase, suggesting a mechanistic role linking the spatial organization of the origins and their activity. Here, we show that Fkh1 and Fkh2 share a unique structural feature of human FoxP proteins that enables FoxP2 and FoxP3 to form domain-swapped dimers capable of bridging two DNA molecules in vitro. Accordingly, Fkh1 self-associates in vitro and in vivo in a manner dependent on the conserved domain-swapping region, strongly suggestive of homodimer formation. Fkh1- and Fkh2-domain-swap-minus (dsm) mutations are functional as transcription factors yet are defective in replication origin timing control. Fkh1-dsm binds replication origins in vivo but fails to cluster them, supporting the conclusion that Fkh1 and Fkh2 dimers perform a structural role in the spatial organization of chromosomal elements with functional importance.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Ostrow, A. Zachary
Kalhor, Reza
Gan, Yan
Villwock, Sandra K.
Linke, Christian
Chen, Lin
Aparicio, Oscar M.
Date : 21 March 2017
DOI : 10.1073/pnas.1612422114
Copyright Disclaimer : Copyright 2017 The Authors
Uncontrolled Keywords : DNA replication timing; Chromatin; Nuclear organization; Fox proteins; DNA binding protein
Depositing User : Diane Maxfield
Date Deposited : 03 Oct 2019 11:52
Last Modified : 03 Oct 2019 11:52

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