Non-homologous end joining: Emerging themes and unanswered questions

Radhakrishnan, Sarvan Kumar; Jette, Nicholas; Lees‐Miller, Susan P.

doi:10.1016/j.dnarep.2014.01.009

Cited by 131 publications

(113 citation statements)

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“…Therefore, factors controlling the method of DNA end resection are critical for the choice between NHEJ and HR in G2 [64,67]. Over the past decades, researchers have been working on identifying the resection control factors, and remarkable progress has been made [10,68].…”

Section: Dsb Resection Directs Competition Between Hr and Nhejmentioning

confidence: 99%

“…DNA-PK complex-dominant DSB detection activates XRCC4-XLF-PAXX-Lig4 signaling and channels the repair into NHEJ in all stages of the cell cycle, whereas MRN complex-dominant DSB recognition initiates 5′-3′ resection by recruiting Mre11, CtIP, Exo1, Dna2, and the single-strand DNA (ssDNA) capture RPA [69], leading to repair via the HR signaling pathway [10]. Competition occurs during G2 phase when both of the repair choices are present.…”

Section: Dsb Resection Directs Competition Between Hr and Nhejmentioning

confidence: 99%

“…Abnormal C-NHEJ signaling is the main cause of chromosome translocation and malignancy [1]. In mammalian cells, the core proteins involved in the C-NHEJ pathway include the Ku70/80 heterodimer (Ku), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), X-ray repair cross-complementing protein 4 (XRCC4), XRCC4-like factor (XLF, also referred to as Cernunnos or NHEJ1), DNA ligase IV (Lig4) [1,10], and the latest discovered protein-PAXX (paralog of XRCC4 and XLF) [11,12] which is also referred to as C9orf142/XLS (XRCC4-like small protein) [13]. The deletion of any of these core C-NHEJ factors is associated with increased radiation sensitivity.…”

Section: Introductionmentioning

confidence: 99%

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Non-homologous end joining: advances and frontiers

Yang

Guo

2016

ABBS

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DNA double-strand breaks (DSBs) are the most serious form of DNA damage. In human cells, non-homologous end joining (NHEJ) is the major pathway for the repair of DSBs. Different types of DSBs result in different subsets of NHEJ repair strategies. These variations in NHEJ repair strategies depend on numerous elements, such as the flexible recruitment of NHEJ-related proteins, the complexity of the DSB ends, and the spatial-and temporal-ordered formation of the multiprotein complex. On the one hand, current studies of DNA DSBs repair focus on the repair pathway choices between homologous recombination and classic or alternative NHEJ. On the other hand, increasing researches have also deepened the significance and dug into the cross-links between the NHEJ pathway and the area of genome organization and aging. Although remarkable progress has been made in elucidating the underlying principles during the past decades, the detailed mechanism of action in response to different types of DSBs remains largely unknown and needs further evaluation in the future study.

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Section: Dsb Resection Directs Competition Between Hr and Nhejmentioning

confidence: 99%

Section: Dsb Resection Directs Competition Between Hr and Nhejmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Non-homologous end joining: advances and frontiers

Yang

Guo

2016

ABBS

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“…Canonical NHEJ: Canonical NHEJ (c-NHEJ) begins with binding and bridging of the ends by DNA-dependent protein kinase (DNA-PK), which consists of the Ku heterodimer (Ku70 and Ku80) and a catalytic subunit (DNA-PK cs ) (reviewed in Radhakrishnan et al 2014). Drosophila has orthologs of Ku70 and Ku80, but DNA-PK cs was lost in Schizophora, Coleoptera, and some other insects, though it is still found in mosquitoes (Table 5).…”

Section: Dsb Repair By Ejmentioning

confidence: 99%

DNA Repair inDrosophila: Mutagens, Models, and Missing Genes

2017

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The numerous processes that damage DNA are counterbalanced by a complex network of repair pathways that, collectively, can mend diverse types of damage. Insights into these pathways have come from studies in many different organisms, including Drosophila melanogaster. Indeed, the first ideas about chromosome and gene repair grew out of Drosophila research on the properties of mutations produced by ionizing radiation and mustard gas. Numerous methods have been developed to take advantage of Drosophila genetic tools to elucidate repair processes in whole animals, organs, tissues, and cells. These studies have led to the discovery of key DNA repair pathways, including synthesis-dependent strand annealing, and DNA polymerase theta-mediated end joining. Drosophila appear to utilize other major repair pathways as well, such as base excision repair, nucleotide excision repair, mismatch repair, and interstrand crosslink repair. In a surprising number of cases, however, DNA repair genes whose products play important roles in these pathways in other organisms are missing from the Drosophila genome, raising interesting questions for continued investigations.

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“…NHEJ is routinely described as an error-prone rejoining process. Whilst NHEJ does not encompass the elegant ability of HR to restore sequence information lost on both DNA strands, the complex DSBs that are associated with such sequence information loss may not arise frequently and c-NHEJ, by interfacing with glycosylases and base excision repair, has the capacity to accurately rejoin DSBs with associated base damage [18][19][20][21]. Sequence information lost on a single DNA strand can be reconstituted by "fill-in" polymerases.…”

Section: Pathways Of End-joining and Their Fidelitymentioning

confidence: 99%

How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability

Jeggo

Löbrich

2015

Biochemical Journal

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DNA DSBs (double-strand breaks) are a significant threat to the viability of a normal cell, since they can result in loss of genetic material if mitosis or replication is attempted in their presence. Consequently, evolutionary pressure has resulted in multiple pathways and responses to enable DSBs to be repaired efficiently and faithfully. Cancer cells, which are under pressure to gain genomic instability, have a striking ability to avoid the elegant mechanisms by which normal cells maintain genomic stability. Current models suggest that, in normal cells, DSB repair occurs in a hierarchical manner that promotes rapid and efficient rejoining first, with the utilization of additional steps or pathways of diminished accuracy if rejoining is unsuccessful or delayed. In the present review, we evaluate the fidelity of DSB repair pathways and discuss how cancer cells promote the utilization of less accurate processes. Homologous recombination serves to promote accuracy and stability during replication, providing a battlefield for cancer to gain instability. Non-homologous end-joining, a major DSB repair pathway in mammalian cells, usually operates with high fidelity and only switches to less faithful modes if timely repair fails. The transition step is finely tuned and provides another point of attack during tumour progression. In addition to DSB repair, a DSB signalling response activates processes such as cell cycle checkpoint arrest, which enhance the possibility of accurate DSB repair. We consider the ways by which cancers modify and hijack these processes to gain genomic instability.

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Non-homologous end joining: Emerging themes and unanswered questions

Abstract: Non-homologous end joining (NHEJ) is the major pathway for the repair of ionizing radiation induced DNA double strand breaks in human cells. Here, we discuss current insights into the mechanism of NHEJ and the interplay between NHEJ and other pathways for repair of IR-induced DNA damage.

Cited by 131 publications

References 131 publications

Non-homologous end joining: advances and frontiers

Non-homologous end joining: advances and frontiers

DNA Repair inDrosophila: Mutagens, Models, and Missing Genes

How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability

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