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

Abstract

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...

Chromosome organization by one-sided and two-sided loop extrusion

“…If yeast condensin is fundamentally different from human condensin in function, its use in cell-free chromosome assembly systems (Shintomi et al, 2017(Shintomi et al, , 2015 should result in long, poorly folded chromosomes relative to those with condensin II only. Similarly, mutations that bias condensin activity towards one-sided extrusion could lead to catastrophic under-compaction of human chromosomes, failure to decatenate chromosomes (Martin et al, 2016) , DNA damage, aneuploidy, developmental disorders (Martin et al, 2016) , and cancer (Mazumdar et al, 2015;Woodward et al, 2016) .…”

Combing Chromosomal DNA Mediated by the SMC Complex: Structure and Mechanisms

“…Therefore, it is possible that the negative regulation by ScpB is linked to the stage of DNA loading. Interestingly, a mutation in mice is found in a similar location in the putative NTD of Caph2 nes , a kleisin subunit of condensin II . This hypomorphic mutation causes tissue‐specific defects in cell proliferation and maintenance of ploidy, potentially being explained by the compromised loading of SMC by the ScpA mutants in vivo .…”

Condensin II inactivation in interphase does not affect chromatin folding or gene expression

“…Supporting the notion that the binding of condensin II to chromosomes contributes to gene regulation, knockdown of NCAPH2 was proposed to lead to down-regulation of genes close to TAD boundaries (Yuen et al, 2017). Several other reports provided circumstantial evidence implicating condensin I and II in the control of gene expression (Kranz et al, 2013;Schuster et al, 2013;Woodward et al, 2016), although the underlying mechanisms might have been indirect in most of these cases. Noteworthy, recent studies suggested the recruitment of condensin complexes to generegulatory elements, notably super-enhancers (Dowen et al, 2013;Li et al, 2015), where they were proposed to contribute to enhancer activation and looping interaction with promoters and sustained expression of cell-identity genes (Dowen et al, 2013).…”