Haploinsufficiency of an RB–E2F1–Condensin II Complex Leads to Aberrant Replication and Aneuploidy

Coschi, Courtney H.; Ishak, Charles A.; Gallo, David; Marshall, Aren E; Talluri, Srikanth; Wang, Jianxin; Cecchini, Matthew J.; Martens, Alison L.; Percy, Vanessa; Welch, Ian; Boutros, Paul C.; Brown, Grant W.; Dick, Frederick A.

doi:10.1158/2159-8290.cd-14-0215

Cited by 76 publications

(106 citation statements)

References 48 publications

(52 reference statements)

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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: 60%

“…a more widespread mechanism that does not require mutations in the core complex (Longworth et al 2008;Coschi et al 2010Coschi et al , 2014Manning et al 2010). Mutations in the Rb tumor suppressor, which is among the most frequently mutated genes in a broad range of human tumors, partially impair condensin II loading and function (Longworth et al 2008;Coschi et al 2010Coschi et al , 2014Manning et al 2010).…”

Section: Discussionmentioning

confidence: 99%

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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: 60%

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…While retinoblastomas resemble other early-childhood cancers in having relatively low numbers of genetic lesions, pan-cancer studies show that mutations in the pRB pathway are associated with tumors that have elevated levels of gene copy number changes (Ciriello et al 2013). Surveys of cell line and genomic data show that loss of one copy of RB1 is associated with an increased level of genome instability (Coschi et al 2014). Thus, the mitotic defects resulting from pRB inactivation may be relevant in many cancers.…”

Section: The Cellular Consequences Of Rb Inactivationmentioning

confidence: 99%

RB1: a prototype tumor suppressor and an enigma

2016

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The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?

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“…Through the physical interaction with these protein factors, pRB is involved in not only local gene promoter inactivation but also global epigenetic control of cellular senescence [21] and differentiation [22]. Furthermore, pRB was recently shown to play a role in DNA replication during the S phase and G2/M phases via interactions with regulator proteins for DNA replication [12, 23], chromatin condensation [24–27], and mitotic spindle formation [28]. Understandably, cellular events, such as G0/G1 maintenance, DNA replication, and mitosis progression, require drastic nuclear structural changes and chromosomal rearrangement.…”

Section: Introductionmentioning

confidence: 99%

“…For example, pRB depletion alters chromatin structure due to changes in epigenetic histone modifications, such as methylation and acetylation, which controls the status in G0/G1 cells [9] or heterochromatin region in the interphase cells [29, 30]. pRB depletion can also cause incomplete chromosomal condensation and segregation in mitosis [24–27]. Importantly, it has been demonstrated that the aberrant chromatin structure and chromosome arrangement caused by pRB inactivation are associated with chromosomal instability [25, 27, 31], which is a hallmark of human cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Roles of pRB in the Regulation of Nucleosome and Chromatin Structures

Uchida

2016

BioMed Research International

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Retinoblastoma protein (pRB) interacts with E2F and other protein factors to play a pivotal role in regulating the expression of target genes that induce cell cycle arrest, apoptosis, and differentiation. pRB controls the local promoter activity and has the ability to change the structure of nucleosomes and/or chromosomes via histone modification, epigenetic changes, chromatin remodeling, and chromosome organization. Functional inactivation of pRB perturbs these cellular events and causes dysregulated cell growth and chromosome instability, which are hallmarks of cancer cells. The role of pRB in regulation of nucleosome/chromatin structures has been shown to link to tumor suppression. This review focuses on the ability of pRB to control nucleosome/chromatin structures via physical interactions with histone modifiers and chromatin factors and describes cancer therapies based on targeting these protein factors.

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Haploinsufficiency of an RB–E2F1–Condensin II Complex Leads to Aberrant Replication and Aneuploidy

Cited by 76 publications

References 48 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

RB1: a prototype tumor suppressor and an enigma

Roles of pRB in the Regulation of Nucleosome and Chromatin Structures

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