The complexity of DNA double strand breaks is a critical factor enhancing end-resection
- PMID: 24041488
- DOI: 10.1016/j.dnarep.2013.08.009
The complexity of DNA double strand breaks is a critical factor enhancing end-resection
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.
Copyright © 2013 Elsevier B.V. All rights reserved.
Similar articles
-
DNA end resection is needed for the repair of complex lesions in G1-phase human cells.Cell Cycle. 2014;13(16):2509-16. doi: 10.4161/15384101.2015.941743. Cell Cycle. 2014. PMID: 25486192 Free PMC article.
-
The complexity of DNA double strand break is a crucial factor for activating ATR signaling pathway for G2/M checkpoint regulation regardless of ATM function.DNA Repair (Amst). 2015 Jan;25:72-83. doi: 10.1016/j.dnarep.2014.11.004. Epub 2014 Nov 24. DNA Repair (Amst). 2015. PMID: 25497328
-
The SWI/SNF ATPase BRG1 stimulates DNA end resection and homologous recombination by reducing nucleosome density at DNA double strand breaks and by promoting the recruitment of the CtIP nuclease.Cell Cycle. 2020 Nov;19(22):3096-3114. doi: 10.1080/15384101.2020.1831256. Epub 2020 Oct 12. Cell Cycle. 2020. PMID: 33044911 Free PMC article.
-
The influence of heterochromatin on DNA double strand break repair: Getting the strong, silent type to relax.DNA Repair (Amst). 2010 Dec 10;9(12):1273-82. doi: 10.1016/j.dnarep.2010.09.013. Epub 2010 Oct 30. DNA Repair (Amst). 2010. PMID: 21036673 Review.
-
Roles for 53BP1 in the repair of radiation-induced DNA double strand breaks.DNA Repair (Amst). 2020 Sep;93:102915. doi: 10.1016/j.dnarep.2020.102915. DNA Repair (Amst). 2020. PMID: 33087281 Review.
Cited by
-
High-complexity of DNA double-strand breaks is key for alternative end-joining choice.Commun Biol. 2024 Aug 3;7(1):936. doi: 10.1038/s42003-024-06640-5. Commun Biol. 2024. PMID: 39095441 Free PMC article.
-
The first real-world study on the role of carbon ion radiotherapy for oligo-metastatic, persistent, or recurrent (MPR) ovarian/fallopian tube cancer.Clin Transl Radiat Oncol. 2024 Apr 20;47:100781. doi: 10.1016/j.ctro.2024.100781. eCollection 2024 Jul. Clin Transl Radiat Oncol. 2024. PMID: 38726346 Free PMC article.
-
A perspective on tumor radiation resistance following high-LET radiation treatment.J Cancer Res Clin Oncol. 2024 May 2;150(5):226. doi: 10.1007/s00432-024-05757-8. J Cancer Res Clin Oncol. 2024. PMID: 38696003 Free PMC article. Review.
-
The impact of DNA double-strand break repair pathways throughout the carbon ion spread-out Bragg peak beam.Cancer Sci. 2023 Dec;114(12):4548-4557. doi: 10.1111/cas.15972. Epub 2023 Oct 3. Cancer Sci. 2023. PMID: 37786999 Free PMC article.
-
DNA damage and repair dependencies of ionising radiation modalities.Biosci Rep. 2023 Oct 31;43(10):BSR20222586. doi: 10.1042/BSR20222586. Biosci Rep. 2023. PMID: 37695845 Free PMC article. Review.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous