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ISRN Molecular Biology
Volume 2012 (2012), Article ID 345805, 16 pages
http://dx.doi.org/10.5402/2012/345805
Review Article

Processing of Damaged DNA Ends for Double-Strand Break Repair in Mammalian Cells

Department of Pharmacology and Toxicology, Virginia Commonwealth University, P.O. Box 980035, Richmond, VA 23298, USA

Received 27 September 2012; Accepted 7 November 2012

Academic Editors: A. Goldar and M. Greenwood

Copyright © 2012 Lawrence F. Povirk. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Most DNA double-strand breaks (DSBs) formed in a natural environment have chemical modifications at or near the ends that preclude direct religation and require removal or other processing so that rejoining can proceed. Free radical-mediated DSBs typically bear unligatable 3′-phosphate or 3′-phosphoglycolate termini and often have oxidized bases and/or abasic sites near the break. Topoisomerase-mediated DSBs are blocked by covalently bound peptide fragments of the topoisomerase. Enzymes capable of resolving damaged ends include polynucleotide kinase/phosphatase, which restores missing 5′-phosphates and removes 3′-phosphates; tyrosyl-DNA phosphodiesterases I and II (TDP1 and TDP2), which remove peptide fragments of topoisomerases I and II, respectively; and the Artemis and Metnase endonucleases, which can trim damaged overhangs of diverse structure. TDP1 as well as APE1 can remove 3′-phosphoglycolates and other 3′ blocks, while CtIP appears to provide an alternative pathway for topoisomerase II fragment removal. Ku, a core DSB joining protein, can cleave abasic sites near DNA ends. The downstream processes of patching and ligation are tolerant of residual damage and can sometimes proceed without complete damage removal. Despite these redundant pathways for resolution, damaged ends appear to be a significant barrier to rejoining, and their resolution may be a rate-limiting step in repair of some DSBs.