Absence of BLM Leads to Accumulation of Chromosomal DNA Breaks during Both Unperturbed and Disrupted S Phases

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,...

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Bibliographic Details
Published in:The Journal of cell biology 2004-06, Vol.165 (6), p.801-812
Main Authors: Li, Wenhui, Kim, Soo-Mi, Lee, Joon, Dunphy, William G.
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - deficiency
Adenosine Triphosphatases - genetics
Animals
Antibodies
Bloom Syndrome - genetics
Cell Nucleus - physiology
Cell Nucleus - ultrastructure
Cellular biology
Chromatin
Chromatin - physiology
Chromatin - ultrastructure
Chromosomes
Deoxyribonucleic acid
DNA
DNA Damage
DNA Helicases - deficiency
DNA Helicases - genetics
DNA replication
Eggs
Female
Humans
Interphase
Male
Methionine - metabolism
Ova
Ovum - cytology
Phosphorylation
Proteins
RecQ Helicases
S Phase - genetics
S Phase - physiology
Spermatozoa
Spermatozoa - cytology
Xenopus
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Summary: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 IIIα (Xtop3α) 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 Xtop3α 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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200402095