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 28 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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“…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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“…Importantly, defects and delays in chromatid condensation are manifested as lagging chromosomes during anaphase that impede mitotic progression, resulting in aneuploidy (Hirota et al 2004;Ono et al 2004;Samoshkin et al 2009). However, there is limited evidence connecting condensin proteins and chromosome condensation to cancer (Ham et al 2007;Lapointe et al 2008).…”

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confidence: 99%

Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive

Coschi

Martens²,

Ritchie³

et al. 2010

Genes Dev.

111

131

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Condensation and segregation of mitotic chromosomes is a critical process for cellular propagation, and, in mammals, mitotic errors can contribute to the pathogenesis of cancer. In this report, we demonstrate that the retinoblastoma protein (pRB), a well-known regulator of progression through the G1 phase of the cell cycle, plays a critical role in mitotic chromosome condensation that is independent of G1-to-S-phase regulation. Using gene targeted mutant mice, we studied this aspect of pRB function in isolation, and demonstrate that it is an essential part of pRB-mediated tumor suppression. Cancer-prone Trp53 À/À mice succumb to more aggressive forms of cancer when pRB's ability to condense chromosomes is compromised. Furthermore, we demonstrate that defective mitotic chromosome structure caused by mutant pRB accelerates loss of heterozygosity, leading to earlier tumor formation in Trp53 +/À mice. These data reveal a new mechanism of tumor suppression, facilitated by pRB, in which genome stability is maintained by proper condensation of mitotic chromosomes.[Keywords: Cohesion; condensation; chromosome instability; cell cycle; chromatin] Supplemental material is available at http://www.genesdev.org.

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Condensin mutations and abnormal chromosomal structures in pyothorax‐associated lymphoma

Cited by 28 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

Condensins: universal organizers of chromosomes with diverse functions

Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive

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