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Absence of BLM leads to accumulation of chromosomal DNA breaks during both unperturbed and disrupted S phases

Li, Wenhui and Kim, Soo-Mi and Lee, Joon and Dunphy, William G. (2004) Absence of BLM leads to accumulation of chromosomal DNA breaks during both unperturbed and disrupted S phases. Journal of Cell Biology, 165 (6). pp. 801-812. ISSN 0021-9525. http://resolver.caltech.edu/CaltechAUTHORS:LIWjcb04

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Abstract

Bloom's syndrome (BS), a disorder associated with genomic instability and cancer predisposition, results from defects in the Bloom's helicase (BLM) protein. In BS cells, chromosomal abnormalities such as sister chromatid exchanges occur at highly elevated rates. Using Xenopus egg extracts, we have studied Xenopus BLM (Xblm) during both unperturbed and disrupted DNA replication cycles. Xblm binds to replicating chromatin and becomes highly phosphorylated in the presence of DNA replication blocks. This phosphorylation depends on Xenopus ATR (Xatr) and Xenopus Rad17 (Xrad17), but not Claspin. Xblm and Xenopus topoisomerase III{alpha} (Xtop3{alpha}) interact in a regulated manner and associate with replicating chromatin interdependently. Immunodepletion of Xblm from egg extracts results in accumulation of chromosomal DNA breaks during both normal and perturbed DNA replication cycles. Disruption of the interaction between Xblm and Xtop3{alpha} has similar effects. The occurrence of DNA damage in the absence of Xblm, even without any exogenous insult to the DNA, may help to explain the genesis of chromosomal defects in BS cells.


Item Type:Article
Additional Information:© The Rockefeller University Press, 2004 Submitted: 18 February 2004; Accepted: 11 May 2004; Published online June 14, 2004. We thank our colleagues in the lab for helpful comments on the manuscript. S.-M. Kim and J. Lee are associates and W.G. Dunphy is an investigator in the Howard Hughes Medical Institute.
Subject Keywords:RecQ helicase; ATR; Rad17; DNA replication; DNA damage
Record Number:CaltechAUTHORS:LIWjcb04
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:LIWjcb04
Alternative URL:http://dx.doi.org/10.1083/jcb.200402095
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:524
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:08 Nov 2006
Last Modified:26 Dec 2012 08:40

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