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Versatility of DNA Double Strand Break Repair | OMICS International
ISSN: 1747-0862
Journal of Molecular and Genetic Medicine
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Versatility of DNA Double Strand Break Repair

Chengtao Her*

School of Molecular Biosciences, College of Veterinary Medicine, USA

Corresponding Author:
Chengtao Her
School of Molecular Biosciences
College of Veterinary Medicine Mail Drop 64-7520
Washington State University, Pullman, WA 99164, USA
Tel: (509) 335-7537
Fax: (509) 335-4159
E-mail: [email protected]

Received date March 24, 2015; Accepted dateMarch 26, 2015; Published date April 02, 2015

Citation: Her C (2015) Versatility of DNA Double Strand Break Repair. J Mol Genet Med 09:e103. doi:10.4172/1747-0862.1000E103

Copyright: © 2015 Her C. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 

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Editorial

The generation of DNA double strand breaks (DSBs) is considered a lethal insult to the integrity of chromosomes. If not repaired, DSBs can lead to daunting consequences such as chromosome fragmentation, deletion, or rearrangement. While a plethora of DSB repair activities are available to cells, inappropriate execution of DSB repair pathways can also be a source for chromosome aberrations. It is proposed that inaccurate joining of DSBs is involved in the generation of the extraordinarily clustered chromosome rearrangements, i.e. chromothripsis, in primary tumors and cancer cell lines [1,2]. Cells are commonly equipped with at least two major DSB repair pathways – homologous recombination (HR) and non-homologous end joining (NHEJ). These two repair pathways are necessitated for the maintenance of genome stability. Although physiologic DSBs are essential for meiosis and immunoglobulin gene rearrangements, the majority of them are pathologic. It is estimated that 10 DSBs can occur in an average human cell per day [3]. Generally, two-ended DSBs are preferred substrates for NHEJ, and the repair of one-ended DSBs can only be carried out by HR [4].

NHEJ represents a major end-joining activity that is available for cells in every phase of the cell cycle, which operates through coordinated actions of Ku70/Ku80, DNA-PKcs, and the ligase complex XRCC4-Ligase IV-XLF [5]. The Ku70/Ku80 heterocomplex protects the break ends from nucleolytic degradation by physically binding to the ends of DSBs and recruiting downstream NHEJ factors [6,7]. DSBs with compatible ends can be ligated directly without end processing; however, incompatible ends have to be processed before rejoining can occur – this process is often associated with deletions or rearrangements at the repair junctions [8-10]. In addition to this welldefined NHEJ pathway, recent evidence suggests the existence of alternative end-joining activities that are normally masked by the canonical pathway [11].

DSBs can also undergo HR-mediated repair; however, HR is commonly confined to the S and G2 phases of the cell cycle in which donor templates are generally available on sister chromatids [12]. HRbased DSB repair is frequently considered to be an “error-free” pathway, but inappropriate execution of HR can also lead to genome alterations. This is largely reflected by the aberrant (ectopic) recombination between repetitive sequences in diseased human genomes [13]. HR initiates from a two-tier 5’-3’ end resection event [14]. The first step is a short end resection carried out by the activities of the MRE11-CtIP complex. This creates a DNA structure that can be processed by a nuclease complex, containing either DNA2 or EXO, to generate long resected ends that are required for HR [15,16]. Repair commences when a homologous donor sequence is identified by the long single-stranded DNA-Rad51 filament. It appears that the short end resection alone is not sufficient to shuttle DSBs towards the HR pathway. In fact, recent evidence indicates that DSBs with short end resections can be rejoined by activities not supported by HR or canonical NHEJ [17-21]. It is conceivable that such end-joining activities can be problematic while maintaining nucleotide sequence fidelity at the repair junctions. It has been increasingly recognized that harnessing long end resection is a key factor in the repair pathway choice for cells at S or G2/M phase [22]. The end resection event is controlled by the interplay between 53BP1 and BRCA, of which 53BP, together with Rif, obstruct end resection and promote NHEJ [23,24]. In contrast, by antagonizing 53BP1’s interaction with DSBs, BRCA1 promotes end resection and ultimately HR-based DSB repair [15]. The outcomes of DSB-inducing anticancer treatments are at least partially dictated by how cancer cells process therapeutic DSBs; therefore, understanding the precise regulation of DSB repair will enable a better prognostic prediction.

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