Direct Microtubule-Binding by Myosin-10 Orients Centrosomes toward Retraction Fibers and Subcortical Actin Clouds.
Developmental Cell 34(3):323 (2015)
Positioning of centrosomes is vital for cell division and development. In metazoan cells, spindle positioning is controlled by a dynamic pool of subcortical actin that organizes in response to the position of retraction fibers. These actin "clouds" are proposed to generate pulling forces on cent...
Chromothripsis from DNA damage in micronuclei.
Nature 522(7555):179 (2015)
Genome sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. Th...
Polyploidy can drive rapid adaptation in yeast.
Nature 519(7543):349 (2015)
Polyploidy is observed across the tree of life, yet its influence on evolution remains incompletely understood. Polyploidy, usually whole-genome duplication, is proposed to alter the rate of evolutionary adaptation. This could occur through complex effects on the frequency or fitness of benefici...
Chromothripsis: A New Mechanism for Rapid Karyotype Evolution.
Genetics 49:183 (2015)
Chromosomal rearrangements are generally thought to accumulate gradually over many generations. However, DNA sequencing of cancer and congenital disorders uncovered a new pattern in which multiple rearrangements arise all at once. The most striking example, chromothripsis, is characterized by te...
From Mutational Mechanisms in Single Cells to Mutational Patterns in Cancer Genomes.
Cold Spring Harbor Symposia on Quantitative Bio... 80:117 (2015)
Analysis of mutations in thousands of cancer genomes has revealed many characteristic patterns of mutagenesis. The search for the molecular mechanisms underlying these mutational patterns has not only generated novel biological insight but also led to the development of new experimental strategi...
Aurea mediocritas: the importance of a balanced genome.
Cold Spring Harbor Perspectives in Biology 6(11):a015842 (2014)
Aneuploidy, defined as an abnormal number of chromosomes, is a hallmark of cancer. Paradoxically, aneuploidy generally has a negative impact on cell growth and fitness in nontransformed cells. In this work, we review recent progress in identifying how aneuploidy leads to genomic and chromosomal ...
Cytokinesis failure triggers hippo tumor suppressor pathway activation.
Cell 158(4):833 (2014)
Genetically unstable tetraploid cells can promote tumorigenesis. Recent estimates suggest that ∼37% of human tumors have undergone a genome-doubling event during their development. This potentially oncogenic effect of tetraploidy is countered by a p53-dependent barrier to proliferation. However,...
Oncogene-like induction of cellular invasion from centrosome amplification.
Nature 510(7503):167 (2014)
Centrosome amplification has long been recognized as a feature of human tumours; however, its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high fr...
Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation.
Nature Genetics 46(6):618 (2014)
Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL), and polysomy 21 is the most frequent somatic aneuploidy among all B-ALLs. Yet the mechanistic links between chromosome 21 triplication and B-ALL remain undefined. Here we show that germline triplicatio...
Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks.
Molecular Cell 54(3):512 (2014)
Excluding 53BP1 from chromatin is required to attenuate the DNA damage response during mitosis, yet the functional relevance and regulation of this exclusion are unclear. Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiq...
Erratum: Parallel genome-scale loss of function screens in 216 cancer cell lines for the identification of context-specific genetic dependencies.
Scientific data 1:140044 (2014)
[This corrects the article DOI: 10.1038/sdata.2014.35.].
Parallel genome-scale loss of function screens in 216 cancer cell lines for the identification of context-specific genetic dependencies.
Scientific data 1:140035 (2014)
Using a genome-scale, lentivirally delivered shRNA library, we performed massively parallel pooled shRNA screens in 216 cancer cell lines to identify genes that are required for cell proliferation and/or viability. Cell line dependencies on 11,000 genes were interrogated by 5 shRNAs per gene. Th...
Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements.
Genes & Development 27(23):2513 (2013)
Recent genome sequencing studies have identified several classes of complex genomic rearrangements that appear to be derived from a single catastrophic event. These discoveries identify ways that genomes can be altered in single large jumps rather than by many incremental steps. Here we compare ...
Microtubule-sliding activity of a kinesin-8 promotes spindle assembly and spindle-length control.
Nature Cell Biology 15(8):948 (2013)
Molecular motors play critical roles in the formation of mitotic spindles, either through controlling the stability of individual microtubules, or by crosslinking and sliding microtubule arrays. Kinesin-8 motors are best known for their regulatory roles in controlling microtubule dynamics. They ...
Inhibition of Cdc42 during mitotic exit is required for cytokinesis.
Journal of Cell Biology 202(2):231 (2013)
The role of Cdc42 and its regulation during cytokinesis is not well understood. Using biochemical and imaging approaches in budding yeast, we demonstrate that Cdc42 activation peaks during the G1/S transition and during anaphase but drops during mitotic exit and cytokinesis. Cdc5/Polo kinase is ...
Linking abnormal mitosis to the acquisition of DNA damage.
Journal of Cell Biology 199(6):871 (2012)
Cellular defects that impair the fidelity of mitosis promote chromosome missegregation and aneuploidy. Increasing evidence reveals that errors in mitosis can also promote the direct and indirect acquisition of DNA damage and chromosome breaks. Consequently, deregulated cell division can devastat...
Move in for the kill: motile microtubule regulators.
Trends in Cell Biology 22(11):567 (2012)
The stereotypical function of kinesin superfamily motors is to transport cargo along microtubules. However, some kinesins also shape the microtubule track by regulating microtubule assembly and disassembly. Recent work has shown that the kinesin-8 family of motors emerge as key regulators of cel...
Regulation of the formin Bnr1 by septins anda MARK/Par1-family septin-associated kinase.
Molecular Biology of the Cell 23(20):4041 (2012)
Formin-family proteins promote the assembly of linear actin filaments and are required to generate cellular actin structures, such as actin stress fibers and the cytokinetic actomyosin contractile ring. Many formin proteins are regulated by an autoinhibition mechanism involving intramolecular bi...
Proteasomal Degradation Resolves Competition between Cell Polarization and Cellular Wound Healing
Cell 150(1):151 (2012)
Cellular wound healing, enabling the repair of membrane damage, is ubiquitous in eukaryotes. One aspect of the wound healing response is the redirection of a polarized cytoskeleton and the secretory machinery to the damage site. Although there has been recent progress in identifying co...
"Two" much of a good thing: telomere damage-induced genome doubling drives tumorigenesis.
Cancer Cell 21(6):712 (2012)
Data from human tumors and mouse models suggest that tetraploidy, one example of polyploidy, can promote tumorigenesis. In this issue of Cancer Cell, Davoli and De Lange make important connections between tetraploidy, tumorigenesis, and telomere crisis-a common event during the development of hu...