%0 Journal Article
%T Processing of Damaged DNA Ends for Double-Strand Break Repair in Mammalian Cells
%A Lawrence F. Povirk
%J ISRN Molecular Biology
%D 2012
%R 10.5402/2012/345805
%X 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 3กไ-phosphate or 3กไ-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 5กไ-phosphates and removes 3กไ-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 3กไ-phosphoglycolates and other 3กไ 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. 1. Introduction DNA double-strand breaks are extremely toxic DNA lesions that arise from a variety of sources, including ionizing radiation [1], radiomimetic drugs [2, 3], oxidative stress [4, 5], abortive or inhibited topoisomerase reactions [6], and immunological processes such as V(D)J and class-switch recombination [7]. Thus, DSB repair is a critical process to which mammalian cells have devoted enormous resources, creating a complex network of repair systems that are intricately linked with cell cycle control and survival/death pathways [7]. Remarkably, molecular mechanisms of DSB repair in mammalian cells almost completely eluded researchers for decades, until the implication of Ku autoantigen in 1994 [8] unleashed a cascade of investigations by which the major players and primary mechanistic details of DSB rejoining were rather rapidly defined. Much of the seminal work elucidating these repair systems has taken advantage of defined DSB substrates, either constructed in vitro or formed in cells by site-specific nucleases [9]. These defined DSBs typically have canonical 5กไ-phosphate and 3กไ-hydroxyl termini suitable for further processing by
%U http://www.hindawi.com/journals/isrn.molecular.biology/2012/345805/