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Nucleic Acids Research 2005 33(1):289-297; doi:10.1093/nar/gki170
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Published online 12 January 2005

© 2005, the authors Nucleic Acids Research, Vol. 33 No. 1 © Oxford University Press 2005; all rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use permissions, please contact journals.permissions{at}oupjournals.org.

Article

Deficiency in 3'-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1)

Tong Zhou, Jae Wan Lee, Haritha Tatavarthi, James R. Lupski2, Kristoffer Valerie1 and Lawrence F. Povirk*

Department of Pharmacology and Toxicology, Virginia Commonwealth University Richmond, VA 23298, USA 1 Department of Radiation Oncology, Virginia Commonwealth University Richmond, VA 23298, USA 2 Department of Molecular and Human Genetics, Baylor College of Medicine Houston, TX 77030, USA

*To whom correspondence should be addressed at Virginia Commonwealth University, PO Box 980230, Richmond, VA 23298-0230, USA. Tel: +1 804 828 9640; Fax: +1 804 828 8079; Email: lpovirk{at}mail2.vcu.edu

Received November 8, 2004. Revised December 16, 2004. Accepted December 16, 2004.

Tyrosyl-DNA phosphodiesterase (TDP1) is a DNA repair enzyme that removes peptide fragments linked through tyrosine to the 3' end of DNA, and can also remove 3'-phosphoglycolates (PGs) formed by free radical-mediated DNA cleavage. To assess whether TDP1 is primarily responsible for PG removal during in vitro end joining of DNA double-strand breaks (DSBs), whole-cell extracts were prepared from lymphoblastoid cells derived either from spinocerebellar ataxia with axonal neuropathy (SCAN1) patients, who have an inactivating mutation in the active site of TDP1, or from closely matched normal controls. Whereas extracts from normal cells catalyzed conversion of 3'-PG termini, both on single-strand oligomers and on 3' overhangs of DSBs, to 3'-phosphate termini, extracts of SCAN1 cells did not process either substrate. Addition of recombinant TDP1 to SCAN1 extracts restored 3'-PG removal, allowing subsequent gap filling on the aligned DSB ends. Two of three SCAN1 lines examined were slightly more radiosensitive than normal cells, but only for fractionated radiation in plateau phase. The results suggest that the TDP1 mutation in SCAN1 abolishes the 3'-PG processing activity of the enzyme, and that there are no other enzymes in cell extracts capable of processing protruding 3'-PG termini. However, the lack of severe radiosensitivity suggests that there must be alternative, TDP1-independent pathways for repair of 3'-PG DSBs.


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