Nuclear compartmentalization of DNA repair

Kalousi, Alkmini; Soutoglou, Evi

doi:10.1016/j.gde.2016.05.013

Cited by 57 publications

(53 citation statements)

References 124 publications

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“…This allows for potential end pairing with a new dsDNA end to find an alternative match should there be more than a single DSB in close proximity. In cells, this search will be governed by the mobility of the DNA ends within the confines of the nucleus, chromosome territory and local chromatin environment (25,26). Given the large platform that NHEJ filaments provide for pairing, it is unlikely that forming new synapsis is a limiting factor.…”

Section: Resultsmentioning

confidence: 99%

Bridging of double-stranded breaks by the nonhomologous end-joining ligation complex is modulated by DNA end chemistry

Reid

Conlin

Yin

et al. 2016

Nucleic Acids Research

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The nonhomologous end-joining (NHEJ) pathway is the primary repair pathway for DNA double strand breaks (DSBs) in humans. Repair is mediated by a core complex of NHEJ factors that includes a ligase (DNA Ligase IV; L4) that relies on juxtaposition of 3΄ hydroxyl and 5΄ phosphate termini of the strand breaks for catalysis. However, chromosome breaks arising from biological sources often have different end chemistries, and how these different end chemistries impact the way in which the core complex directs the necessary transitions from end pairing to ligation is not known. Here, using single-molecule FRET (smFRET), we show that prior to ligation, differences in end chemistry strongly modulate the bridging of broken ends by the NHEJ core complex. In particular, the 5΄ phosphate group is a recognition element for L4 and is critical for the ability of NHEJ factors to promote stable pairing of ends. Moreover, other chemical incompatibilities, including products of aborted ligation, are sufficient to disrupt end pairing. Based on these observations, we propose a mechanism for iterative repair of DSBs by NHEJ.

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Section: Resultsmentioning

confidence: 99%

Bridging of double-stranded breaks by the nonhomologous end-joining ligation complex is modulated by DNA end chemistry

Reid

Conlin

Yin

et al. 2016

Nucleic Acids Research

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“…While evidence suggests that mtDNA molecules are likely to be more susceptible to oxidized DNA damage than nuclear DNA owing to their proximity to sites of oxidative phosphorylation, our current knowledge on the extent of mtDNA damage is limited owing to the lack of experimental approaches to accurately detect oxidatively generated mtDNA damage [7, 12]. Several DNA repair mechanisms exist within a cell to restore DNA integrity and while these pathways have been extensively studied in the nucleus (reviewed in [13, 14]), the base excision repair (BER) pathway has been established as the primary repair pathway in the mitochondrion [15]. Evidence for DNA repair pathways occurring in the mitochondria has been presented where mtDNA repair enzymes are encoded by nuclear genes and translocate to the mitochondria [15, 16].…”

Section: Introductionmentioning

confidence: 99%

DNA damage related crosstalk between the nucleus and mitochondria

Saki

Prakash

2017

Free Radical Biology and Medicine

127

105

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The electron transport chain is the primary pathway by which a cell generates energy in the form of ATP. Byproducts of this process produce reactive oxygen species that can cause damage to mitochondrial DNA. If not properly repaired, the accumulation of DNA damage can lead to mitochondrial dysfunction linked to several human disorders including neurodegenerative diseases and cancer. Mitochondria are able to combat oxidative DNA damage via repair mechanisms that are analogous to those found in the nucleus. Of the repair pathways currently reported in the mitochondria, the base excision repair pathway is the most comprehensively described. Proteins that are involved with the maintenance of mtDNA are encoded by nuclear genes and translocate to the mitochondria making signaling between the nucleus and mitochondria imperative. In this review, we discuss the current understanding of mitochondrial DNA repair mechanisms and also highlight the sensors and signaling pathways that mediate crosstalk between the nucleus and mitochondria in the event of mitochondrial stress.

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“…Intriguingly, DNA break dynamics and pathway choice for repair are interlinked to the chromatin micro-environment surrounding the lesion and to its position within the nucleus (Kalousi & Soutoglou, 2016). DNA breaks within the heterochromatin or the nucleolus, for example, move to the periphery of these compartments to complete repair, while PML bodies appear to be the favorable sites for clustering and repair of a subset of telomeres (Kalousi & Soutoglou, 2016). It is therefore possible that the different physicochemical properties of biomolecular condensates surrounding the damaged DNA and phaseseparated assemblies within various nuclear compartments may account for the observed clustering or exclusion.…”

mentioning

confidence: 99%

53BP1—DNA repair enters a new liquid phase

2019

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In response to DNA damage, transient repair compartments in the nucleus concentrate repair proteins and activate downstream signaling factors. In this issue of The EMBO Journal, Kilic et al show that DNA repair focal assemblies marked by accumulation of 53BP1 are phase separated liquid compartments. This liquid droplet‐like behavior of 53BP1 compartments might help to coordinate local lesion recognition with global gene activation in response to DNA damage.

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Nuclear compartmentalization of DNA repair

Cited by 57 publications

References 124 publications

Bridging of double-stranded breaks by the nonhomologous end-joining ligation complex is modulated by DNA end chemistry

Bridging of double-stranded breaks by the nonhomologous end-joining ligation complex is modulated by DNA end chemistry

DNA damage related crosstalk between the nucleus and mitochondria

53BP1—DNA repair enters a new liquid phase

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