Resolution of Sister Centromeres Requires RanBP2-Mediated SUMOylation of Topoisomerase IIα

Dawlaty, Meelad M.; Malureanu, Liviu; Jeganathan, Karthik B.; Kao, Esther; Sustmann, Claudio; Tahk, Samuel; Shuai, Ke; Grosschedl, Rudolf; Deursen, Jan M. van

doi:10.1016/j.cell.2008.01.045

Cited by 290 publications

(381 citation statements)

References 33 publications

(49 reference statements)

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“…Reduced sumoylation by a hypomorphic allele of a SUMO E3 ligase RanBP2 on Topoisomerase 2 and enhanced chromosomal abnormalities have been causally linked to enhanced tumor formation in a mouse model (58). Our results show, for the first time, that regulation of SUMO E3 ligase by a human oncoprotein results in differential substrate modification and causes an increase of a protein critical for cellular transformation.…”

Section: Discussionmentioning

confidence: 57%

SYT-SSX1 (Synovial Sarcoma Translocated) Regulates PIASy Ligase Activity to Cause Overexpression of NCOA3 Protein

Sun¹,

Perera

Rubin

et al. 2011

Journal of Biological Chemistry

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Chromosomal translocations are a major source of genetic abnormalities causally linked to certain malignancies. Synovial sarcoma is an aggressive soft tissue tumor characterized by a chromosomal translocation between chromosome 18 and X, generating oncoproteins such as SYT-SSX1 and SYT-SSX2. The molecular mechanism underlying the oncogenic potential of SYT-SSX1/2 is not clear. Here we show that SYT-SSX1 leads to up-regulation of NCOA3, a protein critical for the formation of various cancers. The increase of NCOA3 is essential for SYT-SSX1-mediated synovial sarcoma formation. SYT-SSX1 does so by increasing the sumoylation of NCOA3 through interaction with a SUMO E3 ligase, PIASy, as well as the sumoylation of NEMO. NEMO has also been shown to physically interact with NCOA3. Increased sumoylation of NCOA3 leads to its increased steady state level and nuclear localization. Our findings represent the first example that an oncoprotein directly regulates substrate modification by a SUMO E3 ligase, and leads to overexpression of a protein essential for tumor formation. Such a mechanistic finding provides an opportunity to design specific therapeutic interventions to treat synovial sarcoma.

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Section: Discussionmentioning

confidence: 57%

SYT-SSX1 (Synovial Sarcoma Translocated) Regulates PIASy Ligase Activity to Cause Overexpression of NCOA3 Protein

Sun¹,

Perera

Rubin

et al. 2011

Journal of Biological Chemistry

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“…Accumulating evidence suggests Topo II sumoylation promotes sister chromatid decatenation and chromosome segregation in vertebrate cells (Azuma et al, 2003(Azuma et al, , 2005 DiazMartinez et al, 2006;Dawlaty et al, 2008), but whether this modification played an analogous role in yeast Top2 function was unclear. To evaluate functions associated with Top2 sumoylation, we therefore initially compared the catenation status of pRS416, a topologically closed circular minichromosome, in top2-SNM and top2-4 mutants.…”

Section: Sister Chromatid Separation and Segregation In Top2-snm Mutantsmentioning

confidence: 99%

“…We felt this might be informative because in vertebrates sumoylation seems to preferentially promote Topo II function at CENs Dawlaty et al, 2008). CEN dynamics during kinetochore biorientation have been characterized extensively in yeast, primarily using GFP tags integrated immediately adjacent to the kinetochore (Goshima and Yanagida, 2000;He et al, 2000;Tanaka et al, 2000;Pearson et al, 2001).…”

Section: Cen Tensioning In Top2-snm and Top2-4 Mutantsmentioning

confidence: 99%

“…First, in vertebrates Topo II accumulates and exhibits robust activity within mitotic CEN chromatin (reviewed in Porter and Farr, 2004). Sumoylation of Topo II (or possibly other substrates) plays an as yet undefined role in controlling Topo II localization to CENs (Azuma et al, 2005;Diaz-Martinez et al, 2006;Dawlaty et al, 2008). Treatments that block this modification also perturb sister chromatid separation during anaphase, suggesting Topo II CEN targeting helps resolve a final population of topological intertwinings (catenates) so sister CENs can disjoin efficiently.…”

mentioning

confidence: 99%

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DNA Topoisomerase II Is a Determinant of the Tensile Properties of Yeast Centromeric Chromatin and the Tension Checkpoint

Warsi

Navarro

Bachant

2008

MBoC

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Centromeric (CEN) chromatin is placed under mechanical tension and stretches as kinetochores biorient on the mitotic spindle. This deformation could conceivably provide a readout of biorientation to error correction mechanisms that monitor kinetochore-spindle interactions, but whether CEN chromatin acts in a tensiometer capacity is unresolved. Here, we report observations linking yeast Topoisomerase II (Top2) to both CEN mechanics and assessment of interkinetochore tension. First, in top2-4 and sumoylation-resistant top2-SNM mutants CEN chromatin stretches extensively during biorientation, resulting in increased sister kinetochore separation and preanaphase spindle extension. Our data indicate increased CEN stretching corresponds with alterations to CEN topology induced in response to tension. Second, Top2 potentiates aspects of the tension checkpoint. Mutations affecting the Mtw1 kinetochore protein activate Ipl1 kinase to detach kinetochores and induce spindle checkpoint arrest. In mtw1top2-4 and mtw1top2-SNM mutants, however, kinetochores are resistant to detachment and checkpoint arrest is attenuated. For top2-SNM cells, CEN stretching and checkpoint attenuation occur even in the absence of catenation linking sister chromatids. In sum, Top2 seems to play a novel role in CEN compaction that is distinct from decatenation. Perturbations to this function may allow weakened kinetochores to stretch CENs in a manner that mimics tension or evades Ipl1 surveillance. INTRODUCTIONAccurate chromosome segregation requires that sister kinetochores connect to microtubules from opposing poles of the mitotic spindle, a process known as biorientation. Misaligned kinetochore attachments can also occur, and they must be resolved to prevent lethal chromosome segregation errors or the formation of aneuploid cells. Syntelic attachments arise when sister kinetochores connect to microtubules from the same spindle pole; merotelic attachments result if a single kinetochore attaches to both poles. The Aurora-B kinases, complexed with conserved INCENP/ Sli15 and Survivin/Bir1 subunits of the chromosomal passenger complex, are key regulators of the error correction machinery that resolves such inappropriate attachments (reviewed in Ruchaud et al., 2007). Aurora-B (Ipl1 in budding yeast) facilitates error correction through two mechanisms. First, these kinases destabilize defective kinetochore-microtubule interactions by phosphorylating kinetochore-associated proteins. Second, Ipl1/Aurora-B plays a role in activating the spindle assembly checkpoint (SAC), both in response to syntelic attachments as well as mutations that affect the kinetochore or sister chromatid cohesion. Checkpoint activation may occur indirectly because Ipl1/Aurora-B creates unoccupied kinetochores (Pinsky et al., 2006) or directly through phosphorylation of SAC regulators (King et al., 2007).The manner in which Ipl1/Aurora-B distinguishes such a wide range of spindle lesions is not well understood. With the exception of merotelic interactions (Cimini, 2007), those att...

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“…This suggests that RANBP2 plays a crucial role in faithful chromosome segregation, which may provide mechanistic insight into previously reported phenotypes associated with disrupted RANBP2 expression including tumour growth and embryonic lethality in knockout mice [116]. Mice with low levels of RANBP2 were highly sensitive to tumour formation, which is likely due to defective chromosome segregation [118].…”

Section: Cytokinesis Failure and Cancermentioning

confidence: 89%

Cyclophilin function in Cancer; lessons from virus replication

Lavin¹

2015

CMP

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Cyclophilins belong to a group of proteins that possess peptidyl prolyl isomerase activity and catalyse the cis-trans conversion of proline peptide bonds. Cyclophilin members play important roles in protein folding and as molecular chaperones, in addition to a wellestablished role as host factors required for completion of the virus life cycle. Members of the cyclophilin family are overexpressed in a range of human malignancies including hepatocellular cancer, pancreatic cancer, non-small cell lung cancer, gastric cancer, colorectal cancer and glioblastoma multiforme, however, their precise role in tumourigenesis remains unclear. In recent years, mounting evidence supports a role for prolyl isomerisation during mammalian cell division; a process with striking similarity to plasma membrane remodelling during virus replication. Here we will summarise our current understanding of the role of cyclophilins in cancer. We will review the function of cyclophilins during mammalian cell division and during HIV-1 infection, and highlight common processes involving members of the ESCRT and Rab GTPase families. IntroductionThe interconversion of protein backbone between cis and trans, catalysed by peptidyl prolyl isomerases (PPIases), is an important event that alters protein structure and activity and regulates a wide spectrum of cellular functions in normal physiological processes. For example, isomerisation mediates the spatiotemporal control of fundamental processes including cell cycle progression, cell proliferation and cell death [1][2][3][4]. In recent years, mounting evidence implicates deregulated isomerase activity in a range of age-related pathologies including neurodegeneration, cardiovascular disease and cancer [5]. As a result, isomerases have gained significant interest as therapeutic targets in the treatment of these diseases.

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Resolution of Sister Centromeres Requires RanBP2-Mediated SUMOylation of Topoisomerase IIα

Cited by 290 publications

References 33 publications

SYT-SSX1 (Synovial Sarcoma Translocated) Regulates PIASy Ligase Activity to Cause Overexpression of NCOA3 Protein

SYT-SSX1 (Synovial Sarcoma Translocated) Regulates PIASy Ligase Activity to Cause Overexpression of NCOA3 Protein

DNA Topoisomerase II Is a Determinant of the Tensile Properties of Yeast Centromeric Chromatin and the Tension Checkpoint

Cyclophilin function in Cancer; lessons from virus replication

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