Nuclear envelope defects impede a proper response to micronuclear DNA lesions

Terradas, Mariona; Martı́n, Marga; Hernández, Laia; Tusell, Laura; Genescà, Anna

doi:10.1016/j.mrfmmm.2011.09.003

Cited by 60 publications

(54 citation statements)

References 28 publications

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“…These micronuclei are at high risk for the integrity of the genome. First, they exhibit a defective DDR and delayed or defective DNA repair (Terradas et al, 2009, 2012; Crasta et al, 2012). Second, most micronuclei replicate more slowly than the major nucleus and therefore most micronuclei are still replicating when the major nucleus is already in the G2 phase (Crasta et al, 2012).…”

Section: Hr: a Factor Of Genetic Instabilitymentioning

confidence: 99%

Is homologous recombination really an error-free process?

et al. 2014

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Homologous recombination (HR) is an evolutionarily conserved process that plays a pivotal role in the equilibrium between genetic stability and diversity. HR is commonly considered to be error-free, but several studies have shown that HR can be error-prone. Here, we discuss the actual accuracy of HR. First, we present the product of genetic exchanges (gene conversion, GC, and crossing over, CO) and the mechanisms of HR during double strand break repair and replication restart. We discuss the intrinsic capacities of HR to generate genome rearrangements by GC or CO, either during DSB repair or replication restart. During this process, abortive HR intermediates generate genetic instability and cell toxicity. In addition to genome rearrangements, HR also primes error-prone DNA synthesis and favors mutagenesis on single stranded DNA, a key DNA intermediate during the HR process. The fact that cells have developed several mechanisms protecting against HR excess emphasize its potential risks. Consistent with this duality, several pro-oncogenic situations have been consistently associated with either decreased or increased HR levels. Nevertheless, this versatility also has advantages that we outline here. We conclude that HR is a double-edged sword, which on one hand controls the equilibrium between genome stability and diversity but, on the other hand, can jeopardize the maintenance of genomic integrity. Therefore, whether non-homologous end joining (which, in contrast with HR, is not intrinsically mutagenic) or HR is the more mutagenic process is a question that should be re-evaluated. Both processes can be “Dr. Jekyll” in maintaining genome stability/variability and “Mr. Hyde” in jeopardizing genome integrity.

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Section: Hr: a Factor Of Genetic Instabilitymentioning

confidence: 99%

Is homologous recombination really an error-free process?

et al. 2014

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“…Previous work on MN in cultured cells identified functional defects in DNA replication, transcription, DNA damage repair, and nuclear protein localization (Hoffelder et al, 2004; Terradas et al, 2009, 2012; Xu et al, 2011; Crasta et al, 2012). Making a MN does not necessarily decrease functionality as DNA replication occurs normally in karyomeres (i.e.…”

Section: Introductionmentioning

confidence: 99%

“…MN that form during normal development) during embryogenesis in several species (Lemaitre, 1998). In addition, somatic cells MN appear structurally normal (Paulin-Levasseur et al, 1996; Hoffelder et al, 2004), although nuclear pore protein levels appear to be partially decreased (Hoffelder et al, 2004; Crasta et al, 2012; Terradas et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Catastrophic Nuclear Envelope Collapse in Cancer Cell Micronuclei

Hatch

Fischer

Deerinck

et al. 2013

Cell

621

759

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Summary During mitotic exit missegregated chromosomes can recruit their own nuclear envelope (NE) to form micronuclei (MN). MN have reduced functioning compared to primary nuclei in the same cell, although the two compartments appear to be structurally comparable. Here we show that over 60% of MN undergo an irreversible loss of compartmentalization during interphase due to NE collapse. This disruption of the MN, which is induced by defects in nuclear lamina assembly, drastically reduces nuclear functions and can trigger massive DNA damage. MN disruption is associated with chromatin compaction and invasion of endoplasmic reticulum (ER) tubules into the chromatin. We identified disrupted MN in both major subtypes of human non-small cell lung cancer, suggesting that disrupted MN could be a useful objective biomarker for genomic instability in solid tumors. Our study shows that NE collapse is a key event underlying MN dysfunction and establishes a link between aberrant NE organization and aneuploidy.

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“…While much remains to be understood about this process, and its prevalence, it provides strong evidence for links between maintenance of the nuclear compartment and genome integrity. Although loss of nuclear compartmentalization in micronuclei correlates with deficiencies in replication [34], an increase in DNA damage load [33–35], and an altered DNA damage response [36], much remains to be determined about the mechanisms at play.…”

Section: Causes and Consequences Of Nuclear Rupturementioning

confidence: 99%

The nucleus: keeping it together by keeping it apart

Lusk

King

2017

Current Opinion in Cell Biology

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It has been postulated that the segregation of nucleus and cytoplasm supported the development of increased organismal complexity. For example, separating transcription and translation allows for mRNA splicing, while the sequestration of genomic DNA supports the innate immune system’s ability to equate cytoplasmic DNA with pathogens. Consistent with the importance of nucleocytoplasmic compartmentalization in a broad array of cellular processes, defects in maintaining discrete nuclear and cytoplasmic compartments, either due to loss of nuclear pore complex integrity, disrupted nuclear transport or ruptures of the nuclear envelope, lead to cellular dysfunction, cell death and disease. Here, we discuss recent insights into how loss of compartmentalization can arise as well as the consequences for cellular and organismal homeostasis.

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Nuclear envelope defects impede a proper response to micronuclear DNA lesions

Cited by 60 publications

References 28 publications

Is homologous recombination really an error-free process?

Is homologous recombination really an error-free process?

Catastrophic Nuclear Envelope Collapse in Cancer Cell Micronuclei

The nucleus: keeping it together by keeping it apart

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