Structural mechanism of DNA-end synapsis in the non-homologous end joining pathway for repairing double-strand breaks: bridge over troubled ends

Wu, Qian

doi:10.1042/bst20180518

Cited by 10 publications

(15 citation statements)

References 87 publications

(125 reference statements)

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“…The C-terminal domain of Ku80 promotes the recruitment of the DNA-PKcs to form the DNA-PK complex [ 53 ]. DNA-PK can recruit the X-Ray repair cross-complementing protein 4 (XRCC4), XRCC4-like factor (XLF) and the DNA ligase IV to seal the break if the ends are compatible [ 54 , 55 , 56 ]. If the ends are not compatible, DNA-PKcs undergoes self-phosphorylation at the so-called ABCDE cluster and promotes the activation of the Artemis nuclease [ 57 ].…”

Section: Dna Repair Pathwaysmentioning

confidence: 99%

DNA Damage: From Threat to Treatment

Carusillo

Mussolino

2020

Cells

152

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DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of DNA lesions, such as abasic sites, mismatches, interstrand crosslinks, or single-stranded and double-stranded breaks. As a consequence, cells have evolved specialized DNA damage response (DDR) mechanisms to sustain genome integrity. By orchestrating multilayer signaling cascades specific for the type of lesion that occurred, the DDR ensures that genetic information is preserved overtime. In the last decades, DNA repair mechanisms have been thoroughly investigated to untangle these complex networks of pathways and processes. As a result, key factors have been identified that control and coordinate DDR circuits in time and space. In the first part of this review, we describe the critical processes encompassing DNA damage sensing and resolution. In the second part, we illustrate the consequences of partial or complete failure of the DNA repair machinery. Lastly, we will report examples in which this knowledge has been instrumental to develop novel therapies based on genome editing technologies, such as CRISPR-Cas.

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Section: Dna Repair Pathwaysmentioning

confidence: 99%

DNA Damage: From Threat to Treatment

Carusillo

Mussolino

2020

Cells

152

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“…Ku, a tightly associated heterodimer of Ku70 and Ku80 subunits, is the DSB recognition factor of c-NHEJ, binding DSBs with avid affinity, aided by its high abundance in human cells. Structural analysis revealed Ku to be cradle-shaped with the base being substantially thicker [ 1 , 20 ]. The central core can thread onto DSB ends without sequence dependency.…”

Section: Ir-dsbs Within Transcriptionally Active Regions Are Repairedmentioning

confidence: 99%

“…The extensive dimerization interface involves the central core region. Once bound to DNA ends, the larger C-terminal region of Ku80 interacts with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) creating the DNA-PK holoenzyme [ 1 , 21 , 22 ]. Ku binding protects DSB ends from nucleolytic degradation, contributing to a role in regulating pathway choice, since DNA end-resection is a prerequisite for HR [ 23 ].…”

Section: Ir-dsbs Within Transcriptionally Active Regions Are Repairedmentioning

confidence: 99%

“…Canonical or classical DNA non-homologous end-joining (c-NHEJ) and homologous recombination (HR) represent the two major DNA double-strand break (DSB) repair pathways. c-NHEJ is a relatively simple process involving factors that co-ordinate DNA end synapsis and protection, DNA end-processing and ligation (see [ 1 , 2 ] for reviews). HR has also been extensively reviewed and will only be outlined here [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Roles for the DNA-PK complex and 53BP1 in protecting ends from resection during DNA double-strand break repair

Shibata

Jeggo²

2020

Journal of Radiation Research

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p53-binding protein 1 (53BP1) exerts distinct impacts in different situations involving DNA double-strand break (DSB) rejoining. Here we focus on how 53BP1 impacts upon the repair of ionising radiation-induced DSBs (IR-DSBs) and how it interfaces with Ku, the DNA end-binding component of canonical non-homologous end-joining (c-NHEJ), the major DSB repair pathway in mammalian cells. We delineate three forms of IR-DSB repair: resection-independent c-NHEJ, which rejoins most IR-DSBs with fast kinetics in G1 and G2, and Artemis and resection-dependent c-NHEJ and homologous recombination (HR), which repair IR-DSBs with slow kinetics in G1 and G2 phase, respectively. The fast component of DSB repair after X-ray exposure occurs via c-NHEJ with normal kinetics in the absence of 53BP1. Ku is highly abundant and has avid DNA end-binding capacity which restricts DNA end-resection and promotes resection-independent c-NHEJ at most IR-DSBs. Thus, 53BP1 is largely dispensable for resection-independent c-NHEJ. In contrast, 53BP1 is essential for the process of rejoining IR-DSBs with slow kinetics. This role requires 53BP1’s breast cancer susceptibility gene I (BRCA1) C-terminal (BRCT) 2 domain, persistent ataxia telangiectasia mutated (ATM) activation and potentially relaxation of compacted chromatin at heterochromatic-DSBs. In distinction, 53BP1 inhibits resection-dependent IR-DSB repair in G1 and G2, and this resection-inhibitory function can be counteracted by BRCA1. We discuss a model whereby most IR-DSBs are rapidly repaired by 53BP1-independent and resection-independent c-NHEJ due to the ability of Ku to inhibit resection, but, if delayed, then resection in the presence of Ku is triggered, the 53BP1 barrier comes into force and BRCA1 counteraction is required for resection.

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“…A series of eight proteins have been identified as the critical NHEJ components, which are involved in the ligation of DNA-dsb [ 11 ]. The DNA-binding subunits Ku70 and Ku80 together form a ring shaped heterodimer that acts as an anchor protein binding the DNA ends and protecting them from exonucleolytic activity.…”

Section: Molecular Pathwaysmentioning

confidence: 99%

Update on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency

Slatter

Gennery

2020

Curr Allergy Asthma Rep

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Purpose of Review The most serious DNA damage, DNA double strand breaks (DNA-dsb), leads to mutagenesis, carcinogenesis or apoptosis if left unrepaired. Non-homologous end joining (NHEJ) is the principle repair pathway employed by mammalian cells to repair DNA-dsb. Several proteins are involved in this pathway, defects in which can lead to human disease. This review updates on the most recent information available for the specific diseases associated with the pathway. Recent Findings A new member of the NHEJ pathway, PAXX, has been identified, although no human disease has been associated with it. The clinical phenotypes of Artemis, DNA ligase 4, Cernunnos-XLF and DNA-PKcs deficiency have been extended. The role of haematopoietic stem cell transplantation, following reduced intensity conditioning chemotherapy, for many of these diseases is being advanced. Summary In the era of newborn screening, urgent genetic diagnosis is necessary to correctly target appropriate treatment for patients with DNA-dsb repair disorders.

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Structural mechanism of DNA-end synapsis in the non-homologous end joining pathway for repairing double-strand breaks: bridge over troubled ends

Cited by 10 publications

References 87 publications

DNA Damage: From Threat to Treatment

DNA Damage: From Threat to Treatment

Roles for the DNA-PK complex and 53BP1 in protecting ends from resection during DNA double-strand break repair

Update on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency

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