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1.  Kinetochore–microtubule attachment throughout mitosis potentiated by the elongated stalk of the kinetochore kinesin CENP-E 
Molecular Biology of the Cell  2014;25(15):2272-2281.
CENP-E kinesin harbors a highly elongated coiled-coil stalk. Using in vitro and in vivo approaches, we characterize a “Bonsai” version of CENP-E with a shortened stalk. We show that the stalk positively regulates CENP-E's motor activity, which is required for maintenance of kinetochore–microtubule attachments in both metaphase and anaphase.
Centromere protein E (CENP-E) is a highly elongated kinesin that transports pole-proximal chromosomes during congression in prometaphase. During metaphase, it facilitates kinetochore–microtubule end-on attachment required to achieve and maintain chromosome alignment. In vitro CENP-E can walk processively along microtubule tracks and follow both growing and shrinking microtubule plus ends. Neither the CENP-E–dependent transport along microtubules nor its tip-tracking activity requires the unusually long coiled-coil stalk of CENP-E. The biological role for the CENP-E stalk has now been identified through creation of “Bonsai” CENP-E with significantly shortened stalk but wild-type motor and tail domains. We demonstrate that Bonsai CENP-E fails to bind microtubules in vitro unless a cargo is contemporaneously bound via its C-terminal tail. In contrast, both full-length and truncated CENP-E that has no stalk and tail exhibit robust motility with and without cargo binding, highlighting the importance of CENP-E stalk for its activity. Correspondingly, kinetochore attachment to microtubule ends is shown to be disrupted in cells whose CENP-E has a shortened stalk, thereby producing chromosome misalignment in metaphase and lagging chromosomes during anaphase. Together these findings establish an unexpected role of CENP-E elongated stalk in ensuring stability of kinetochore–microtubule attachments during chromosome congression and segregation.
PMCID: PMC4116301  PMID: 24920822
2.  TDP-43 toxicity: the usefulness of “junk” 
Nature genetics  2012;44(12):1289-1291.
Loss of the lariat debranching enzyme Dbr1 is found to repress TDP-43 toxicity. The accumulated intronic lariat RNAs, which are normally degraded after splicing, likely act as decoys to sequester TDP-43 away from binding to and disrupting function of other RNAs.
PMCID: PMC3612973  PMID: 23192178
3.  Centrosomes, chromosome instability (CIN) and aneuploidy 
Current opinion in cell biology  2012;24(6):809-815.
Each time a cell divides its chromosome content must be equally segregated into the two daughter cells. This critical process is mediated by a complex microtubule based apparatus, the mitotic spindle. In most animal cells the centrosomes contribute to the formation and the proper function of the mitotic spindle by anchoring and nucleating microtubules and by establishing its functional bipolar organization. Aberrant expression of proteins involved in centrosome biogenesis can drive centrosome dysfunction or abnormal centrosome number, leading ultimately to improper mitotic spindle formation and chromosome missegregation. Here we review recent work focusing on the importance of the centrosome for mitotic spindle formation and the relation between the centrosome status and the mechanisms controlling faithful chromosome inheritance.
PMCID: PMC3621708  PMID: 23127609
4.  Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis 
Neuron  2012;74(6):1031-1044.
The primary cause of Huntington’s disease (HD) is expression of huntingtin with a polyglutamine expansion. Despite an absence of consensus on the mechanism(s) of toxicity, diminishing the synthesis of mutant huntingtin will abate toxicity if delivered to the key affected cells. With antisense oligonucleotides (ASOs) that catalyze RNase H-mediated degradation of huntingtin mRNA, we demonstrate that transient infusion into the cerebral spinal fluid of symptomatic HD mouse models not only delays disease progression, but mediates a sustained reversal of disease phenotype that persists longer than the huntingtin knockdown. Reduction of wild type huntingtin, along with mutant huntingtin, produces the same sustained disease reversal. Similar ASO infusion into non-human primates is shown to effectively lower huntingtin in many brain regions targeted by HD pathology. Rather than requiring continuous treatment, our findings establish a therapeutic strategy for sustained HD disease reversal produced by transient ASO-mediated diminution of huntingtin synthesis.
PMCID: PMC3383626  PMID: 22726834
5.  Neurodegeneration 
Nature  2008;454(7202):284-285.
That mutations in the SOD1 enzyme underlie familial form of the motor neuron disease ALS is clear. But there seems to be more than one answer to the question of what are the consequences of such mutations.
PMCID: PMC3625042  PMID: 18633404
6.  Polo-like kinase 4 controls centriole duplication but does not directly regulate cytokinesis 
Molecular Biology of the Cell  2012;23(10):1838-1845.
Polo-like kinase 4 (Plk4) plays an essential role in centriole duplication, but recent work led to the conclusion that Plk4 also directly regulates cytokinesis. The consequence of reduced Plk4 levels in human and mouse cells is studied. It is shown that Plk4 controls centriole duplication but does not directly regulate cytokinesis.
Centrioles organize the centrosome, and accurate control of their number is critical for the maintenance of genomic integrity. Centrioles duplicate once per cell cycle, and duplication is coordinated by Polo-like kinase 4 (Plk4). We previously demonstrated that Plk4 accumulation is autoregulated by its own kinase activity. However, loss of heterozygosity of Plk4 in mouse embryonic fibroblasts has been proposed to cause cytokinesis failure as a primary event, leading to centrosome amplification and gross chromosomal abnormalities. Using targeted gene disruption, we show that human epithelial cells with one inactivated Plk4 allele undergo neither cytokinesis failure nor increase in centrosome amplification. Plk4 is shown to localize exclusively at the centrosome, with none in the spindle midbody. Substantial depletion of Plk4 by small interfering RNA leads to loss of centrioles and subsequent spindle defects that lead to a modest increase in the rate of cytokinesis failure. Therefore, Plk4 is a centriole-localized kinase that does not directly regulate cytokinesis.
PMCID: PMC3350549  PMID: 22456511
7.  The quantitative architecture of centromeric chromatin 
eLife  2014;3:e02137.
The centromere, responsible for chromosome segregation during mitosis, is epigenetically defined by CENP-A containing chromatin. The amount of centromeric CENP-A has direct implications for both the architecture and epigenetic inheritance of centromeres. Using complementary strategies, we determined that typical human centromeres contain ∼400 molecules of CENP-A, which is controlled by a mass-action mechanism. This number, despite representing only ∼4% of all centromeric nucleosomes, forms a ∼50-fold enrichment to the overall genome. In addition, although pre-assembled CENP-A is randomly segregated during cell division, this amount of CENP-A is sufficient to prevent stochastic loss of centromere function and identity. Finally, we produced a statistical map of CENP-A occupancy at a human neocentromere and identified nucleosome positions that feature CENP-A in a majority of cells. In summary, we present a quantitative view of the centromere that provides a mechanistic framework for both robust epigenetic inheritance of centromeres and the paucity of neocentromere formation.
eLife digest
The genetic information in a cell is packed into structures called chromosomes. These contain strands of DNA wrapped around proteins called histones, which helps the long DNA chains to fit inside the relatively small nucleus of the cell.
When a cell divides, it is important that both of the new cells contain all of the genetic information found in the parent cell. Therefore, the chromosomes duplicate during cell division, with the two copies held together at a single region of the chromosome called the centromere. The centromere then recruits and coordinates the molecular machinery that separates the two copies into different cells.
Centromeres are inherited in an epigenetic manner. This means that there is no specific DNA sequence that defines the location of this structure on the chromosomes. Rather, a special type of histone, called CENP-A, is involved in defining its location. Bodor et al. use multiple techniques to show that human centromeres normally contain around 400 molecules of CENP-A, and that this number is crucial for ensuring that centromeres form in the right place. Interestingly, only a minority of the CENP-A molecules are located at centromeres; yet this is more than at any other region of the chromosome. This explains why centromeres are only formed at a single position on each chromosome.
When the chromosomes separate, the CENP-A molecules at the centromere are randomly divided between the two copies. In this way memory of the centromere location is maintained. If the number of copies of CENP-A inherited by one of the chromosomes drops below a threshold value, a centromere will not form. However, Bodor et al. found that the number of CENP-A molecules in a centromere is large enough, not only to support the formation of the centromere structure, but also to keep it above the threshold value in nearly all cases. This threshold is also high enough to make it unlikely that a centromere will form in the wrong place because of a random fluctuation in the number of CENP-A molecules. Therefore, the number of CENP-A molecules is crucial for controlling both the formation and the inheritance of the centromere.
PMCID: PMC4091408  PMID: 25027692
centromere; CENP-A; epigenetics; molecular counting; quantitative microscopy; histone variant; human
8.  Catalytic Assembly of the Mitotic Checkpoint Inhibitor BubR1-Cdc20 by Mad2-induced Functional Switch in Cdc20 
Molecular cell  2013;51(1):92-104.
The mitotic checkpoint acts to maintain chromosome content by generation of a diffusible anaphase inhibitor. Unattached kinetochores catalyze a conformational shift in Mad2, converting an inactive open form into a closed one that can capture Cdc20, the mitotic activator of the APC/C ubiquitin ligase. Mad2 binding is now shown to promote a functional switch in Cdc20, exposing a previously inaccessible site for binding to BubR1’s conserved Mad3 homology domain. BubR1, but not Mad2, binding to APC/CCdc20 is demonstrated to inhibit ubiquitination of cyclin B. Closed Mad2 is further shown to catalytically amplify production of BubR1-Cdc20 without necessarily being part of the complex. Thus, the mitotic checkpoint is produced by a cascade of two catalytic steps, an initial one acting at unattached kinetochores to produce a diffusible Mad2-Cdc20 intermediate and a diffusible one in which that intermediate amplifies production of BubR1-Cdc20, the inhibitor of cyclin B ubiquitination by APC/CCdc20.
PMCID: PMC3713096  PMID: 23791783
9.  How to survive aneuploidy 
Cell  2010;143(1):27-29.
Aneuploidy, or the abnormal number of chromosomes, adversely effects cell growth, but it is also linked with cancer and tumorigenesis. Now Torres et al. (2010) help resolve this paradox by demonstrating that aneuploid yeast cells can evolve mutations in the proteasome protein degradation pathway that alleviate imbalances in protein production and increase the cell’s proliferative capacities.
PMCID: PMC2955074  PMID: 20887888
10.  Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43 
Nature neuroscience  2011;14(4):459-468.
Cross-linking and immunoprecipitation coupled with high-throughput sequencing was used to identify binding sites within 6,304 genes as the brain RNA targets for TDP-43, an RNA binding protein which when mutated causes Amyotrophic Lateral Sclerosis (ALS). Use of massively parallel sequencing and splicing-sensitive junction arrays revealed that levels of 601 mRNAs are changed (including Fus/Tls, progranulin, and other transcripts encoding neurodegenerative disease-associated proteins) and 965 altered splicing events are detected (including in sortilin, the receptor for progranulin), following depletion of TDP-43 from mouse adult brain with antisense oligonucleotides. RNAs whose levels are most depleted by reduction in TDP-43 are derived from genes with very long introns and which encode proteins involved in synaptic activity. Lastly, TDP-43 was found to auto-regulate its synthesis, in part by directly binding and enhancing splicing of an intron within the 3′ untranslated region of its own transcript, thereby triggering nonsense mediated RNA degradation. (147 words)
PMCID: PMC3094729  PMID: 21358643
11.  Multi-classifier proteomics to define complexes yields new chromosomal proteins 
Developmental cell  2010;19(3):356-359.
In a recent issue of Cell, Ohta et al. (2010) report a method of quantitative proteomics coupled with bioinformatic analysis for the identification of associated components in complex mixtures. Using this approach, they assayed the protein composition of mitotic chromosomes, identifying 4029 associated proteins, 562 of which are previously uncharacterized.
PMCID: PMC2943763  PMID: 20833356
12.  Misfolded Mutant SOD1 Directly Inhibits VDAC1 Conductance in a Mouse Model of Inherited ALS 
Neuron  2010;67(4):575-587.
Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons. With conformation specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane. This interaction is found on isolated spinal cord mitochondria and can be reconstituted with purified components in vitro. ADP passage through the outer membrane is diminished in spinal mitochondria from mutant SOD1-expressing ALS rats. Direct binding of mutant SOD1 to VDAC1 inhibits conductance of individual channels when reconstituted in a lipid bilayer. Reduction of VDAC1 activity with targeted gene disruption is shown to diminish survival by accelerating onset of fatal paralysis in mice expressing the ALS-causing mutation SOD1G37R. Taken together, our results establish a direct link between misfolded mutant SOD1 and mitochondrial dysfunction in this form of inherited ALS.
PMCID: PMC2941987  PMID: 20797535
13.  Centriole duplication 
Cell Cycle  2010;9(14):2731-2736.
In interphase and mitosis, centrosomes play a major role in the spatial organization of the microtubule network. Alterations in centrosome number and structure are associated with genomic instability and occur in many cancers. Centrosome duplication is controlled by centriole replication. In most dividing animal cells, centrioles duplicate only once per cell cycle at a site adjacent to existing centrioles. The conserved protein kinase Polo-like kinase 4 (Plk4) has a key role in controlling centriole biogenesis. Overexpression of Plk4 drives centrosome amplification and is associated with tumorigenesis in flies. By contrast, haploinsufficiency of Plk4 promotes cytokinesis failure, leading to an increased incidence of tumors in mice. Recent studies have shown that Plk4 is a low abundance protein whose stability is linked to the activity of the enzyme. We discuss how this autoregulatory feedback loop acts to limit the damaging effects caused by too much or too little Plk4.
PMCID: PMC3040958  PMID: 20647763
centrosome; centriole; polo-like kinase 4; Plk4; SAK; SCF; phosphodegron; β-TrCP; aneuploidy
14.  NuMA after 30 years: the Matrix Revisited 
Trends in cell biology  2010;20(4):214-222.
The large Nuclear Mitotic Apparatus (NuMA) protein is an abundant component of interphase nuclei and an essential player in mitotic spindle assembly and maintenance. With its partner, cytoplasmic dynein, NuMA uses its cross-linking properties to tether microtubules to spindle poles. NuMA and its invertebrate homologues play a similar tethering role at the cell cortex, thereby mediating essential asymmetric divisions during development. Despite its maintenance as a nuclear component for decades after the final mitosis of many cell types (including neurons), an interphase role for NuMA remains to be established, although its structural properties implicate it as a component of a nuclear scaffold, perhaps as a central constituent of the proposed nuclear matrix.
PMCID: PMC3137513  PMID: 20137953
15.  Glial cells as intrinsic components of non-cell autonomous neurodegenerative disease 
Nature neuroscience  2007;10(11):1355-1360.
A lesson from dominantly inherited forms of diverse neurodegenerative diseases, including amyotrophic lateral sclerosis, spinocerebellar ataxia and Huntington’s disease, is that the selective dysfunction or death of the neuronal population most at risk in each disease is not mediated solely by mutant derived damage within the target neurons. The disease-causing toxic process, which in each case is caused by mutation in a gene that is widely or ubiquitously expressed, involves mutant damage within the non-neuronal glial cells of the central nervous system - especially astrocytes and microglia. Disease mechanism is non-cell autonomous, with toxicity derived from glia as a prominent contributor to driving disease progression and in some instances even disease initiation.
PMCID: PMC3110080  PMID: 17965655
16.  A chemical tool box defines mitotic and interphase roles for Mps1 kinase 
The Journal of Cell Biology  2010;190(1):21-24.
In this issue, three groups (Hewitt et al. 2010. J. Cell Biol. doi:10.1083/jcb.201002133; Maciejowski et al. 2010. J. Cell Biol. doi:10.1083/jcb.201001050; Santaguida et al. 2010. J. Cell Biol. doi:10.1083/jcb.201001036) use chemical inhibitors to analyze the function of the mitotic checkpoint kinase Mps1. These studies demonstrate that Mps1 kinase activity ensures accurate chromosome segregation through its recruitment to kinetochores of mitotic checkpoint proteins, formation of interphase and mitotic inhibitors of Cdc20, and correction of faulty microtubule attachments.
PMCID: PMC2911672  PMID: 20624898
17.  Kinetochore kinesin CENP-E is a processive bi-directional tracker of dynamic microtubule tips 
Nature cell biology  2013;15(9):1079-1088.
During vertebrate mitosis, the centromere-associated kinesin CENP-E transports misaligned chromosomes to the plus ends of spindle microtubules. Subsequently, the kinetochores that form at the centromeres establish stable associations with microtubule ends, which assemble and disassemble dynamically. Here we provide evidence that after chromosomes have congressed and bi-oriented, the CENP-E motor continues to play an active role at kinetochores, enhancing their links with dynamic microtubule ends. Using a combination of single molecule approaches and laser trapping in vitro we demonstrate that once reaching microtubule ends, CENP-E converts from a lateral transporter into a microtubule tip-tracker which maintains association with both assembling and disassembling microtubule tips. Computational modeling of this behavior supports our proposal that CENP-E tip-tracks bi-directionally via a “tethered motor” mechanism, which relies on both the motor and tail domains of CENP-E. Our results provide a molecular framework for CENP-E's contribution to the stability of attachments between kinetochores and dynamic microtubule ends.
PMCID: PMC3919686  PMID: 23955301
18.  Polo-like kinase 4 kinase activity limits centrosome overduplication by autoregulating its own stability 
The Journal of Cell Biology  2010;188(2):191-198.
Plk4 phosphorylates itself in trans to prevent accumulation and self-limit kinase activity, which may be important for regulating centriole duplication.
Accurate control of the number of centrosomes, the major microtubule-organizing centers of animal cells, is critical for the maintenance of genome integrity. Abnormalities in centrosome number can promote errors in spindle formation that lead to subsequent chromosome missegregation, and extra centrosomes are found in many cancers. Centrosomes are comprised of a pair of centrioles surrounded by amorphous pericentriolar material, and centrosome duplication is controlled by centriole replication. Polo-like kinase 4 (Plk4) plays a key role in initiating centriole duplication, and overexpression of Plk4 promotes centriole overduplication and the formation of extra centrosomes. Using chemical genetics, we show that kinase-active Plk4 is inherently unstable and targeted for degradation. Plk4 is shown to multiply self-phosphorylate within a 24–amino acid phosphodegron. Phosphorylation of multiple sites is required for Plk4 instability, indicating a requirement for a threshold level of Plk4 kinase activity to promote its own destruction. We propose that kinase-mediated, autoregulated instability of Plk4 self-limits Plk4 activity so as to prevent centrosome amplification.
PMCID: PMC2813471  PMID: 20100909
19.  Centromere specific assembly of CENP-A nucleosomes is mediated by HJURP 
Cell  2009;137(3):472-484.
The centromere is responsible for accurate chromosome segregation. Mammalian centromeres are specified epigenetically, with all active centromeres containing centromere specific chromatin in which CENP-A replaces histone H3 within the nucleosome. The proteins responsible for assembly of human CENP-A into centromeric nucleosomes during the G1 phase of the cell cycle are now identified to be distinct from the chromatin assembly factors that load other histone H3 variants. Prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1 and HJURP. Recruitment of new CENP-A into nucleosomes at replicated centromeres is dependent on HJURP. Recognition by HJURP is mediated through the centromere targeting domain (CATD) of CENP-A, a region that induces a unique conformational rigidity to both the subnucleosomal CENP-A heterotetramer and the corresponding assembled nucleosome. We propose HJURP to be a cell cycle regulated CENP-A specific histone chaperone required for centromeric chromatin assembly.
PMCID: PMC2747366  PMID: 19410544
20.  Unattached Kinetochores Catalyze Production of an Anaphase Inhibitor that Requires a Mad2 Template to Prime Cdc20 for BubR1 Binding 
Developmental cell  2009;16(1):105-117.
Premature anaphase onset is prevented by the mitotic checkpoint through production of a “wait anaphase” inhibitor(s) that blocks recognition of cyclin B and securin by Cdc20-activated APC/C, an E3 ubiquitin ligase which targets them for destruction. Using physiologically-relevant levels of Mad2, Bub3, BubR1, and Cdc20, we demonstrate that unattached kinetochores on purified chromosomes catalytically generate a diffusible Cdc20 inhibitor or inhibit Cdc20 already bound to APC/C. Furthermore, the chromosome-produced inhibitor requires both recruitment of Mad2 by Mad1 that is stably bound at unattached kinetochores and dimerization-competent Mad2. We show that purified chromosomes promote BubR1 binding to APC/C-Cdc20 by acting directly on Mad2, but not BubR1. Our results support a model in which immobilized Mad1/Mad2 at kinetochores provides a template for initial assembly of Mad2 bound to Cdc20 that is then converted to a final mitotic checkpoint inhibitor with Cdc20 bound to BubR1.
PMCID: PMC2655205  PMID: 19154722
21.  Phosphorylation of Highly Conserved Neurofilament Medium KSP Repeats Is Not Required for Myelin-Dependent Radial Axonal Growth 
Neurofilament medium (NF-M) is essential for the acquisition of normal axonal caliber in response to a myelin-dependent “outside-in” trigger for radial axonal growth. Removal of the tail domain and lysine-serine-proline (KSP) repeats of NF-M, but not neurofilament heavy, produced axons with impaired radial growth and reduced conduction velocities. These earlier findings supported myelin-dependent phosphorylation of NF-MKSP repeats as an essential component of axonal growth. As a direct test of whether phosphorylation of NF-M KSP repeats is the target for the myelin-derived signal, gene replacement has now been used to produce mice in which all serines of NF-M’s KSP repeats have been replaced with phosphorylation-incompetent alanines. This substitution did not alter accumulation of the neurofilaments or their subunits. Axonal caliber and motor neuron conduction velocity of mice expressing KSP phospho-incompetent NF-M were also indistinguishable from wild-type mice. Thus, phosphorylation of NF-M KSP repeats is not an essential component for the acquisition of normal axonal caliber mediated by myelin-dependent outside-in signaling.
PMCID: PMC2782950  PMID: 19193875
neurofilaments; cytoskeleton; myelination; radial growth; motor neuron; phosphorylation
22.  Requirements for NuMA in maintenance and establishment of mammalian spindle poles 
The Journal of Cell Biology  2009;184(5):677-690.
Microtubules of the mitotic spindle in mammalian somatic cells are focused at spindle poles, a process thought to include direct capture by astral microtubules of kinetochores and/or noncentrosomally nucleated microtubule bundles. By construction and analysis of a conditional loss of mitotic function allele of the nuclear mitotic apparatus (NuMA) protein in mice and cultured primary cells, we demonstrate that NuMA is an essential mitotic component with distinct contributions to the establishment and maintenance of focused spindle poles. When mitotic NuMA function is disrupted, centrosomes provide initial focusing activity, but continued centrosome attachment to spindle fibers under tension is defective, and the maintenance of focused kinetochore fibers at spindle poles throughout mitosis is prevented. Without centrosomes and NuMA, initial establishment of spindle microtubule focusing completely fails. Thus, NuMA is a defining feature of the mammalian spindle pole and functions as an essential tether linking bulk microtubules of the spindle to centrosomes.
PMCID: PMC2686415  PMID: 19255246
23.  CENP-E combines a slow, processive motor and a flexible coiled coil to produce an essential motile kinetochore tether 
The Journal of Cell Biology  2008;181(3):411-419.
The mitotic kinesin centromere protein E (CENP-E) is an essential kinetochore component that directly contributes to the capture and stabilization of spindle microtubules by kinetochores. Although reduction in CENP-E leads to high rates of whole chromosome missegregation, neither its properties as a microtubule-dependent motor nor how it contributes to the dynamic linkage between kinetochores and microtubules is known. Using single-molecule assays, we demonstrate that CENP-E is a very slow, highly processive motor that maintains microtubule attachment for long periods. Direct visualization of full-length Xenopus laevis CENP-E reveals a highly flexible 230-nm coiled coil separating its kinetochore-binding and motor domains. We also show that full-length CENP-E is a slow plus end–directed motor whose activity is essential for metaphase chromosome alignment. We propose that the highly processive microtubule-dependent motor activity of CENP-E serves to power chromosome congression and provides a flexible, motile tether linking kinetochores to dynamic spindle microtubules.
PMCID: PMC2364708  PMID: 18443223
24.  Mechanisms and consequences of localized, complex chromosomal rearrangements in cancer and developmental diseases 
Nature medicine  2012;18(11):1630-1638.
Next-generation DNA sequencing of human tumors has led to discovery of chromoanagenesis, in which large numbers of complex rearrangements occur at one or a few chromosomal loci in a single catastrophic event. Two mechanisms underlie these rearrangements, both of which can be facilitated by a mitotic chromosome segregation error to produce a micronucleus containing the chromosome to undergo rearrangement. In the first, chromosome shattering (called chromothripsis) is produced by mitotic entry before completion of DNA replication within the micronucleus, with failure to disassemble the micronuclear envelope encapsulating the chromosomal fragments for random reassembly in the subsequent interphase. Alternatively, locally defective DNA replication (also potentially within a micronucleus) initiates serial, microhomology-mediated template switching (called chromoanasynthesis) that produces local rearrangements with altered gene copy numbers. Complex, localized rearrangements are present in a broad spectrum of tumors and in individuals with congenital or developmental defects, highlighting the impact of chromoanagenesis in human disease.
PMCID: PMC3616639  PMID: 23135524
25.  Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis 
Nature neuroscience  2013;16(5):571-579.
Oligodendrocytes associate with axons to establish myelin and provide metabolic support to neurons. In the spinal cord of ALS mice, oligodendrocytes downregulate transporters that transfer glycolytic substrates to neurons and oligodendrocyte progenitors (NG2+ cells) exhibit enhanced proliferation and differentiation, although the cause of these changes in oligodendroglia is unknown. Here we report that there is extensive degeneration of gray matter oligodendrocytes in the spinal cord of ALS mice before disease onset. Although new oligodendrocytes were formed, they failed to mature, resulting in progressive demyelination. Oligodendrocyte dysfunction also is prevalent in human ALS, as gray matter demyelination and reactive changes in NG2+ cells were observed in motor cortex and spinal cord of ALS patients. Selective removal of mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival in ALS mice, suggesting that ALS-linked genes enhance the vulnerability of motor neurons and accelerate disease by directly impairing the function of oligodendrocytes.
PMCID: PMC3637847  PMID: 23542689

Results 1-25 (81)