Nucleolus and nuclear periphery: Velcro for heterochromatin

Padeken, Jan; Heun, Patrick

doi:10.1016/j.ceb.2014.03.001

Cited by 158 publications

(147 citation statements)

References 53 publications

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“…To gain insight into the cause of the DDR delay and HR repression promoted by the nuclear lamina environment, we considered the possibility that the repressive chromatin structure associated with the nuclear lamina (Padeken and Heun 2014) is involved in this phenomenon (Goodarzi and Jeggo 2012;Lemaître and Soutoglou 2014).…”

Section: Resultsmentioning

confidence: 99%

Nuclear position dictates DNA repair pathway choice

et al. 2014

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Faithful DNA repair is essential to avoid chromosomal rearrangements and promote genome integrity. Nuclear organization has emerged as a key parameter in the formation of chromosomal translocations, yet little is known as to whether DNA repair can efficiently occur throughout the nucleus and whether it is affected by the location of the lesion. Here, we induce DNA double-strand breaks (DSBs) at different nuclear compartments and follow their fate. We demonstrate that DSBs induced at the nuclear membrane (but not at nuclear pores or nuclear interior) fail to rapidly activate the DNA damage response (DDR) and repair by homologous recombination (HR). Real-time and superresolution imaging reveal that DNA DSBs within lamina-associated domains do not migrate to more permissive environments for HR, like the nuclear pores or the nuclear interior, but instead are repaired in situ by alternative end-joining. Our results are consistent with a model in which nuclear position dictates the choice of DNA repair pathway, thus revealing a new level of regulation in DSB repair controlled by spatial organization of DNA within the nucleus.

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Section: Resultsmentioning

confidence: 99%

Nuclear position dictates DNA repair pathway choice

et al. 2014

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“…This altered morphology appears to be reversible (Krystosek 1998). Finally, a number of non-NOR-bearing chromosomes and chromosomal domains that can associate with the PNH have been identified in nucleolar genomics and immuno-FISH experiments (for review, see Nemeth and Langst 2011;Padeken and Heun 2014).…”

Section: The Nucleolar Cyclementioning

confidence: 99%

Nucleolar organizer regions: genomic ‘dark matter’ requiring illumination

2016

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Nucleoli form around tandem arrays of a ribosomal gene repeat, termed nucleolar organizer regions (NORs). During metaphase, active NORs adopt a characteristic undercondensed morphology. Recent evidence indicates that the HMG-box-containing DNA-binding protein UBF (upstream binding factor) is directly responsible for this morphology and provides a mitotic bookmark to ensure rapid nucleolar formation beginning in telophase in human cells. This is likely to be a widely employed strategy, as UBF is present throughout metazoans. In higher eukaryotes, NORs are typically located within regions of chromosomes that form perinucleolar heterochromatin during interphase. Typically, the genomic architecture of NORs and the chromosomal regions within which they lie is very poorly described, yet recent evidence points to a role for context in their function. In Arabidopsis, NOR silencing appears to be controlled by sequences outside the rDNA (ribosomal DNA) array. Translocations reveal a role for context in the expression of the NOR on the X chromosome in Drosophila. Recent work has begun on characterizing the genomic architecture of human NORs. A role for distal sequences located in perinucleolar heterochromatin has been inferred, as they exhibit a complex transcriptionally active chromatin structure. Links between rDNA genomic stability and aging in Saccharomyces cerevisiae are now well established, and indications are emerging that this is important in aging and replicative senescence in higher eukaryotes. This, combined with the fact that rDNA arrays are recombinational hot spots in cancer cells, has focused attention on DNA damage responses in NORs. The introduction of DNA double-strand breaks into rDNA arrays leads to a dramatic reorganization of nucleolar structure. Damaged rDNA repeats move from the nucleolar interior to form caps at the nucleolar periphery, presumably to facilitate repair, suggesting that the chromosomal context of human NORs contributes to their genomic stability. The inclusion of NORs and their surrounding chromosomal environments in future genome drafts now becomes a priority.The relationship between nucleolar organizer regions (NORs) and nucleoli was first established in the 1930s (Heitz 1931;McClintock 1934), but, for decades, the content of the former and the role of the latter remained mysterious. The era of molecular and cellular biology revealed that NORs contain tandem arrays of ribosomal gene (rDNA) repeats and that nucleoli are the sites of ribosome biogenesis. Biochemistry has revealed the inner workings of the nucleolus and the complexity of ribosome biogenesis (for review, see Pederson 2010). However, the genomic architecture of NORs and the chromosomal context in which they lie remains undetermined for most eukaryotes. The resulting void has placed limitations on our understanding of the fundamental mechanisms by which NORs orchestrate formation of the largest structure in the nucleus. In this review, I discuss recent findings regarding the morphology of active NORs and how they seed r...

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“…This is consistent with the late and gradual accumulation of these methyl marks described above. adjacent to the nuclear lamina and the periphery of the nucleoli (Padeken and Heun 2014). The unique nuclear position has been suggested to play a role during the establishment of heterochromatin (Jachowicz et al 2013).…”

Section: Ordering the Events During Heterochromatinizationmentioning

confidence: 99%

TALE-light imaging reveals maternally guided, H3K9me2/3-independent emergence of functional heterochromatin in Drosophila embryos

Yuan

O’Farrell

2016

Genes Dev.

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Metazoans start embryogenesis with a relatively naïve genome. The transcriptionally inert, late-replicating heterochromatic regions, including the constitutive heterochromatin on repetitive sequences near centromeres and telomeres, need to be re-established during development. To explore the events initiating heterochromatin formation and examine their temporal control, sequence specificity, and immediate regulatory consequence, we established a live imaging approach that enabled visualization of steps in heterochromatin emergence on specific satellite sequences during the mid-blastula transition (MBT) in Drosophila. Unexpectedly, only a subset of satellite sequences, including the 359-base-pair (bp) repeat sequence, recruited HP1a at the MBT. The recruitment of HP1a to the 359-bp repeat was dependent on HP1a's chromoshadow domain but not its chromodomain and was guided by maternally provided signals. HP1a recruitment to the 359-bp repeat was required for its programmed shift to later replication, and ectopic recruitment of HP1a was sufficient to delay replication timing of a different repeat. Our results reveal that emergence of constitutive heterochromatin follows a stereotyped developmental program in which different repetitive sequences use distinct interactions and independent pathways to arrive at a heterochromatic state. This differential emergence of heterochromatin on various repetitive sequences changes their replication order and remodels the DNA replication schedule during embryonic development.

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Nucleolus and nuclear periphery: Velcro for heterochromatin

Cited by 158 publications

References 53 publications

Nuclear position dictates DNA repair pathway choice

Nuclear position dictates DNA repair pathway choice

Nucleolar organizer regions: genomic ‘dark matter’ requiring illumination

TALE-light imaging reveals maternally guided, H3K9me2/3-independent emergence of functional heterochromatin in Drosophila embryos

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