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. 2013 Nov;12(11):936-46.
doi: 10.1016/j.dnarep.2013.08.009. Epub 2013 Sep 13.

The complexity of DNA double strand breaks is a critical factor enhancing end-resection

Hirohiko Yajima  1 , Hiroshi Fujisawa, Nakako Izumi Nakajima, Hirokazu Hirakawa, Penelope A Jeggo, Ryuichi Okayasu, Akira Fujimori
Affiliations

The complexity of DNA double strand breaks is a critical factor enhancing end-resection

Hirohiko Yajima et al. DNA Repair (Amst). 2013 Nov.

Abstract

DNA double strand breaks (DSBs) induced by ionizing radiation (IR) are deleterious damages. Two major pathways repair DSBs in human cells, DNA non-homologous end-joining (NHEJ) and homologous recombination (HR). It has been suggested that the balance between the two repair pathways varies depending on the chromatin structure surrounding the damage site and/or the complexity of damage at the DNA break ends. Heavy ion radiation is known to induce complex-type DSBs, and the efficiency of NHEJ in repairing these DSBs was shown to be diminished. Taking advantage of the ability of high linear energy transfer (LET) radiation to produce complex DSBs effectively, we investigated how the complexity of DSB end structure influences DNA damage responses. An early step in HR is the generation of 3'-single strand DNA (SSD) via a process of DNA end resection that requires CtIP. To assess this process, we analyzed the level of phosphorylated CtIP, as well as RPA phosphorylation and focus formation, which occur on the exposed SSD. We show that complex DSBs efficiently activate DNA end resection. After heavy ion beam irradiation, resection signals appear both in the vicinity of heterochromatic areas, which is also observed after X-irradiation, and additionally in euchromatic areas. Consequently, ~85% of complex DSBs are subjected to resection in heavy ion particle tracks. Furthermore, around 20-40% of G1 cells exhibit resection signals. Taken together, our observations reveal that the complexity of DSB ends is a critical factor regulating the choice of DSB repair pathway and drastically alters the balance toward resection-mediated rejoining. As demonstrated here, studies on DNA damage responses induced by heavy ion radiation provide an important tool to shed light on mechanisms regulating DNA end resection.

Keywords: 4′,6-diamidino-2-phenylindole.; ATM; CENP-F; CPT; CtIP; DAPI; DNA double strand breaks; DNA end resection; DSBs; HR; IR; LET; MEF; MMEJ; PIKK; RBE; RPA; camptothecin; centromere protein F; complex DNA damage structure; homologous recombination; ionizing radiation; linear energy transfer; micro homology-mediated end joining; mouse embryonic fibroblast; phosphatidyl inositol 3′ kinase-related kinase; relative biological effectiveness; replication protein A.

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