Condensin mutations and abnormal chromosomal structures in pyothorax‐associated lymphoma

Ham, Maria Francisca; Takakuwa, Tetsuya; Rahadiani, Nur; Tresnasari, Kristianti; Nakajima, Hiroo; Aozasa, Katsuyuki

doi:10.1111/j.1349-7006.2007.00500.x

Cited by 29 publications

(33 citation statements)

References 26 publications

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“…In this study, we provide experimental support for the hypothesis that condensin dysfunction can promote tumorigenesis (Ham et al 2007;Longworth et al 2008;Coschi et al 2010Coschi et al , 2014Manning et al 2010;Hirano 2012). We found that tumors initiate from thymic T cells progressing from the DN to DP stage, which allowed us to characterize the cellular abnormalities that precede and therefore presumably drive Caph2-dependent malignancy.…”

Section: Discussionsupporting

confidence: 61%

Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability

et al. 2016

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Chromosomal instability is a hallmark of cancer, but mitotic regulators are rarely mutated in tumors. Mutations in the condensin complexes, which restructure chromosomes to facilitate segregation during mitosis, are significantly enriched in cancer genomes, but experimental evidence implicating condensin dysfunction in tumorigenesis is lacking. We report that mice inheriting missense mutations in a condensin II subunit (Caph2 nes ) develop T-cell lymphoma. Before tumors develop, we found that the same Caph2 mutation impairs ploidy maintenance to a different extent in different hematopoietic cell types, with ploidy most severely perturbed at the CD4 + CD8 + T-cell stage from which tumors initiate. Premalignant CD4 + CD8 + T cells show persistent catenations during chromosome segregation, triggering DNA damage in diploid daughter cells and elevated ploidy. Genome sequencing revealed that Caph2 singlemutant tumors are near diploid but carry deletions spanning tumor suppressor genes, whereas P53 inactivation allowed Caph2 mutant cells with whole-chromosome gains and structural rearrangements to form highly aggressive disease. Together, our data challenge the view that mitotic chromosome formation is an invariant process during development and provide evidence that defective mitotic chromosome structure can promote tumorigenesis.[Keywords: chromosome structure; condensin; genome instability; lymphoma; mitosis] Supplemental material is available for this article. Received May 23, 2016; revised version accepted September 15, 2016. Genome integrity is maintained by molecular machines that drive the duplication and segregation of the genome and by checkpoints that monitor for incorrect execution of these processes. As cells enter mitosis, chromosomes undergo profound structural changes, which are driven by topoisomerase II and condensins (Swedlow and Hirano 2003). This process removes catenations between sister chromatids, generates stiff rod-like structures that are competent for chromosome segregation, and is essential for genome propagation through the cell cycle in all eukaryotes.Condensins belong to the structural maintenance of chromosomes (SMC) complex family that also includes cohesin and SMC5/6. In eukaryotes, each SMC complex contains a heterodimer of SMC ATPase subunits, a single kleisin subunit, and additional accessory factors (Fig 1A;Losada and Hirano 2005;Nasmyth and Haering 2005). Within cohesin and condensin complexes, the C and N termini of kleisin interact with apposing SMC subunits to form a tripartite, asymmetric ring-like structure that can entrap DNA (Gruber et al. 2003;Onn et al. 2007;Nasmyth and Oliveira 2010;Cuylen et al. 2011; Piazza et al. Cold Spring Harbor Laboratory Press on May 10, 2018 -Published by genesdev.cshlp.org Downloaded from 2014). This mode of association has been proposed to allow SMC complexes to form topological linkages between chromosomes or different regions on the same DNA molecule.Metazoan genomes encode at least two distinct condensin complexes (Ono et al. 2003), whi...

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Section: Discussionsupporting

confidence: 61%

Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability

et al. 2016

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“…Such trends will undoubtedly continue in the years to come. It will also be important to determine to what extent mutations or misregulation of cohesin and condensin subunits might contribute to human cancers (Ham et al 2007;Balbás-Martínez et al 2013;Guo et al 2013;Kon et al 2013;Solomon et al 2013). Third, and, finally, all issues described above need to be addressed, also, from an evolutionary point of view.…”

Section: Discussionmentioning

confidence: 99%

Chromosome Dynamics during Mitosis

Hirano

2015

Cold Spring Harb Perspect Biol

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The primary goal of mitosis is to partition duplicated chromosomes into daughter cells. Eukaryotic chromosomes are equipped with two distinct classes of intrinsic machineries, cohesin and condensins, that ensure their faithful segregation during mitosis. Cohesin holds sister chromatids together immediately after their synthesis during S phase until the establishment of bipolar attachments to the mitotic spindle in metaphase. Condensins, on the other hand, attempt to "resolve" sister chromatids by counteracting cohesin. The products of the balancing acts of cohesin and condensins are metaphase chromosomes, in which two rod-shaped chromatids are connected primarily at the centromere. In anaphase, this connection is released by the action of separase that proteolytically cleaves the remaining population of cohesin. Recent studies uncover how this series of events might be mechanistically coupled with each other and intricately regulated by a number of regulatory factors.

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“…Although no direct evidence for this idea has been reported so far, potentially interesting observations can be found in the literature. For instance, somatic point mutations in the SMC2/CAP-E and SMC4/CAP-C subunits have been identified in several cases of pyothoraxassociated lymphoma in humans (Ham et al 2007). In zebrafish, a mutation in the condensin I CAP-G subunit increases genomic imbalances and the rate of apoptosis in the retina (Seipold et al 2009).…”

Section: Cancers and Tissue Growthmentioning

confidence: 99%

Condensins: universal organizers of chromosomes with diverse functions

2012

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Condensins are multisubunit protein complexes that play a fundamental role in the structural and functional organization of chromosomes in the three domains of life. Most eukaryotic species have two different types of condensin complexes, known as condensins I and II, that fulfill nonoverlapping functions and are subjected to differential regulation during mitosis and meiosis. Recent studies revealed that the two complexes contribute to a wide variety of interphase chromosome functions, such as gene regulation, recombination, and repair. Also emerging are their cell type- and tissue-specific functions and relevance to human disease. Biochemical and structural analyses of eukaryotic and bacterial condensins steadily uncover the mechanisms of action of this class of highly sophisticated molecular machines. Future studies on condensins will not only enhance our understanding of chromosome architecture and dynamics, but also help address a previously underappreciated yet profound set of questions in chromosome biology.

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Condensin mutations and abnormal chromosomal structures in pyothorax‐associated lymphoma

Cited by 29 publications

References 26 publications

Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability

Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability

Chromosome Dynamics during Mitosis

Condensins: universal organizers of chromosomes with diverse functions

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