Haploinsufficiency of the mSds3 chromatin regulator promotes chromosomal instability and cancer only upon complete neutralization of p53

Gourichon, David; Dannenberg, Jan-Hermen; Simpson, Natalie E.; Finnerty, Patricia M.; Miao, Lili; Turner, G. M.; Ding, Zhihu; Carrasco, Ruben D.; DePinho, Ronald A.

doi:10.1038/sj.onc.1209734

Cited by 13 publications

(11 citation statements)

References 26 publications

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“…Overexpression of CENP-A has been linked to CIN in colon tumors and causes chromosome mis-segregation in colon cancer cells (Tomonaga et al, 2003;Amato et al, 2009). In model organisms, disruption of the pathways which maintain pericentromeric heterochromatin has been linked to chromosome mis-segregation and cancer (Bernard et al, 2001;Peters et al, 2001;David et al, 2003;David et al, 2006;Bourgo et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Potential candidates include mis-expression of the SUV39H1/2 methyltransferases whose inactivation in mice eliminates pericentromeric H3K9me3 and drives CIN, and tumorigenesis (Peters et al, 2001). In addition, pRb, one of the most frequently mutated genes in human cancer, as well as the chromatin remodeling complexes SWI/SNF and mSds3, are all required for faithful chromosome segregation and tumor suppression and have been implicated in the maintenance of pericentromeric heterochromatin and H3K9 methylation (David et al, 2003;Gonzalo et al, 2005;David et al, 2006;Bourgo et al, 2009;Sullivan et al, 2011).…”

Section: Pericentromeric Heterochromatin Changes In Cancer Rb Slee Et Almentioning

confidence: 99%

“…The function of the centromere is therefore vulnerable to disruption of the pathways that maintain this unique chromatin architecture. CENP-A overexpression is seen in breast and colon cancer and has been linked to a CIN phenotype (Perou et al, 2000;Tomonaga et al, 2003;Amato et al, 2009), and engineered disruption of pericentromeric heterochromatin is associated with chromosome mis-segregation and tumorigenesis (Ekwall et al, 1997;Bernard et al, 2001;Peters et al, 2001;David et al, 2003;Shin et al, 2003;Gonzalo et al, 2005;David et al, 2006;Bourgo et al, 2009). Furthermore, targeting of chromatin modifiers to human artificial chromosomes disrupts centromere function (Nakano et al, 2008;Cardinale et al, 2009;Bergmann et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability

et al. 2011

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Many tumors exhibit elevated chromosome mis-segregation termed chromosome instability (CIN), which is likely to be a potent driver of tumor progression and drug resistance. Causes of CIN are poorly understood but probably include prior genome tetraploidization, centrosome amplification and mitotic checkpoint defects. This study identifies epigenetic alteration of the centromere as a potential contributor to the CIN phenotype. The centromere controls chromosome segregation and consists of higher-order repeat (HOR) alpha-satellite DNA packaged into two chromatin domains: the kinetochore, harboring the centromere-specific H3 variant centromere protein A (CENP-A), and the pericentromeric heterochromatin, considered important for cohesion. Perturbation of centromeric chromatin in model systems causes CIN. As cancer cells exhibit widespread chromatin changes, we hypothesized that pericentromeric chromatin structure could also be affected, contributing to CIN. Cytological and chromatin immunoprecipitation and PCR (ChIP-PCR)-based analyses of HT1080 cancer cells showed that only one of the two HORs on chromosomes 5 and 7 incorporate CENP-A, an organization conserved in all normal and cancer-derived cells examined. Contrastingly, the heterochromatin marker H3K9me3 (trimethylation of H3 lysine 9) mapped to all four HORs and ChIP-PCR showed an altered pattern of H3K9me3 in cancer cell lines and breast tumors, consistent with a reduction on the kinetochore-forming HORs. The JMJD2B demethylase is overexpressed in breast tumors with a CIN phenotype, and overexpression of exogenous JMJD2B in cultured breast epithelial cells caused loss of centromere-associated H3K9me3 and increased CIN. These findings suggest that impaired maintenance of pericentromeric heterochromatin may contribute to CIN in cancer and be a novel therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Section: Pericentromeric Heterochromatin Changes In Cancer Rb Slee Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability

et al. 2011

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“…Phenotypic effects caused by gene haploinsufficiency (monoallelic expression and heterozygosis) have been described in mutants affected in diverse components of the chromatin-remodeling machinery (Bultman et al, 2000;Roberts et al, 2000;Alarcon et al, 2004;David et al, 2006). For instance, heterozygous mice that have a single copy of either BRG1 (the mammalian orthologous gene of the yeast Swi2/Snf2 ATPase) or SNF5 (a core component of the SWI/SNF complex) are predisposed to different tumors, indicating that a full dosage of both BRG1 and SNF5 is required for proper control of gene expression and tumor suppression (Bultman et al, 2000;Roberts et al, 2000).…”

Section: In Planta Interaction Between Hab1 and Swi3bmentioning

confidence: 99%

HAB1–SWI3B Interaction Reveals a Link between Abscisic Acid Signaling and Putative SWI/SNF Chromatin-Remodeling Complexes in Arabidopsis

et al. 2008

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Abscisic acid (ABA) has an important role for plant growth, development, and stress adaptation. HYPERSENSITIVE TO ABA1 (HAB1) is a protein phosphatase type 2C that plays a key role as a negative regulator of ABA signaling; however, the molecular details of HAB1 action in this process are not known. A two-hybrid screen revealed that SWI3B, an Arabidopsis thaliana homolog of the yeast SWI3 subunit of SWI/SNF chromatin-remodeling complexes, is a prevalent interacting partner of HAB1. The interaction mapped to the N-terminal half of SWI3B and required an intact protein phosphatase catalytic domain. Bimolecular fluorescence complementation and coimmunoprecipitation assays confirmed the interaction of HAB1 and SWI3B in the nucleus of plant cells. swi3b mutants showed a reduced sensitivity to ABA-mediated inhibition of seed germination and growth and reduced expression of the ABA-responsive genes RAB18 and RD29B. Chromatin immunoprecipitation experiments showed that the presence of HAB1 in the vicinity of RD29B and RAB18 promoters was abolished by ABA, which suggests a direct involvement of HAB1 in the regulation of ABA-induced transcription. Additionally, our results uncover SWI3B as a novel positive regulator of ABA signaling and suggest that HAB1 modulates ABA response through the regulation of a putative SWI/SNF chromatin-remodeling complex.

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“…Interestingly, loss of chromatin regulatory proteins can have deleterious effects on chromatin structure that can compromise genome stability and fuel tumorigenesis (David et al, 2003(David et al, , 2006. Here, we used somatic cell culture models to define the impact of the SWI/SNF chromatin-modifying complex on chromatin biology and cell cycle progression.…”

Section: Introductionmentioning

confidence: 99%

SWI/SNF Deficiency Results in Aberrant Chromatin Organization, Mitotic Failure, and Diminished Proliferative Capacity

Bourgo

Siddiqui

Fox

et al. 2009

MBoC

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Switch (SWI)/sucrose nonfermentable (SNF)is an evolutionarily conserved complex with ATPase function, capable of regulating nucleosome position to alter transcriptional programs within the cell. It is known that the SWI/SNF complex is responsible for regulation of many genes involved in cell cycle control and proliferation, and it has recently been implicated in cancer development. The ATPase action of SWI/SNF is conferred through either the brahma-related gene 1 (Brg1) or brahma (Brm) subunit of the complex, and it is of central importance to the modification of nucleosome position. In this study, the role of the Brg1 and Brm subunits were examined as they relate to chromatin structure and organization. Deletion of the Brg1 ATPase results in dissolution of pericentromeric heterochromatin domains and a redistribution of histone modifications associated with these structures. This effect was highly specific to Brg1 and is not reproduced by the loss of Brm or SNF5/BAF47/INI1. Brg1 deficiency is associated with the appearance of micronuclei and aberrant mitoses that are a by-product of dissociated chromatin structure. Thus, Brg1 plays a critical role in maintaining chromatin structural integrity. INTRODUCTIONThe switch/sucrose nonfermentable (SWI/SNF) complex uses the energy of ATP hydrolysis to modulate nucleosome position and density across promoters and thus plays an important role in regulating gene expression. The SWI/SNF ATPase function is necessary for its chromatin remodeling activities (Laurent et al., 1993), and this function is manifested through one of two mutually exclusive subunits, brahma-related gene 1 (Brg1) or brahma (Brm). Although both Brg1 and Brm can function as the central ATPase in the SWI/SNF complex, each defines a discrete complex with unique biochemical activity. In addition, specific accessory factors interact with the ATPase subunits and play critical roles in chromatin remodeling activity. For example, SNF5/ BAF47/INI1 is present in both Brg1-and Brm-associated complexes and is required for maximal chromatin remodeling activity, both in vitro and in yeast. Surprisingly, although Brg1 and Brm have Ͼ75% sequence homology, the impact of each individual subunit on chromatin biology and underlying cell biology is poorly understood (Phelan et al., 1999).Due to its central function in chromatin remodeling, SWI/ SNF function is required in many facets of gene regulation. Correspondingly, it is estimated that approximately 5% of the yeast genome is transcriptionally regulated by the SWI/ SNF complex (Holstege et al., 1998;Sudarsanam et al., 2000). In mammalian cells, SWI/SNF plays a critical role in the activation of a diverse set of genes and has been shown to be recruited directly to transcriptional activation domains (De- Hassan et al., 2001). In contrast, SWI/ SNF is also required for transcriptional repression. For example, transcriptional repression of cell cycle genes mediated by the retinoblastoma tumor suppressor is dependent on SWI/SNF, implicating the involvement of SWI/SNF in cell...

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Haploinsufficiency of the mSds3 chromatin regulator promotes chromosomal instability and cancer only upon complete neutralization of p53

Cited by 13 publications

References 26 publications

Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability

Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability

HAB1–SWI3B Interaction Reveals a Link between Abscisic Acid Signaling and Putative SWI/SNF Chromatin-Remodeling Complexes in Arabidopsis

SWI/SNF Deficiency Results in Aberrant Chromatin Organization, Mitotic Failure, and Diminished Proliferative Capacity

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