Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres

Remeseiro, Silvia; Cuadrado, Ana; Carretero, María; Martínez, Paula; Drosopoulos, William C.; Cañamero, Marta; Schildkraut, Carl L.; Blasco, Marı́a A.; Losada, Ana

doi:10.1038/emboj.2012.11

Cited by 162 publications

(211 citation statements)

References 69 publications

(97 reference statements)

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“…Similar results were obtained in mouse cells deleted for SA1 (Remeseiro et al, 2012a). The need for specialized cohesion at telomeres is likely due to the repetitive G-rich structure, which poses problems for replication fork progression, leading to nicks and gaps that must be repaired prior to mitosis.…”

Section: Introductionsupporting

confidence: 73%

SA1 binds directly to DNA via its unique AT-hook to promote sister chromatid cohesion at telomeres

Bisht

Daniloski

Smith

2013

Journal of Cell Science

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SummarySister chromatid cohesion relies on cohesin, a complex comprising a tri-partite ring and a peripheral subunit Scc3, which is found as two related isoforms SA1 and SA2 in vertebrates. There is a division of labor between the vertebrate cohesin complexes; SA1-cohesin is required at telomeres and SA2-cohesin at centromeres. Depletion of SA1 has dramatic consequences for telomere function and genome integrity, but the mechanism by which SA1-cohesin mediates cohesion at telomeres is not well understood. Here we dissect the individual contribution of SA1 and the ring subunits to telomere cohesion and show that telomeres rely heavily on SA1 and to a lesser extent on the ring for cohesion. Using chromatin immunoprecipitation we show that SA1 is highly enriched at telomeres, is decreased at mitosis when cohesion is resolved, and is increased when cohesion persists. Overexpression of SA1 alone was sufficient to induce cohesion at telomeres, independent of the cohesin ring and dependent on its unique (not found in SA2) N-terminal domain, which we show binds to telomeric DNA through an AT-hook motif. We suggest that a specialized cohesion mechanism may be required to accommodate the high level of DNA replication-associated repair at telomeres.

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Section: Introductionsupporting

confidence: 73%

SA1 binds directly to DNA via its unique AT-hook to promote sister chromatid cohesion at telomeres

Bisht

Daniloski

Smith

2013

Journal of Cell Science

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“…Although 90% of solid tumors display whole-chromosome aneuploidy, it is not clear what role aneuploidy plays in transformation and cancer progression. In mouse models, chromosomal instability (CIN) can both instigate and inhibit tumorigenesis (33,(38)(39)(40)(41). In human patients, CIN in tumor cells is generally associated with aggressive disease (42), although in some contexts high levels of CIN actually correlate with improved prognosis (43).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional consequences of aneuploidy

Sheltzer

Torres

Dunham

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

251

265

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Aneuploidy, or an aberrant karyotype, results in developmental disabilities and has been implicated in tumorigenesis. However, the causes of aneuploidy-induced phenotypes and the consequences of aneuploidy on cell physiology remain poorly understood. We have performed a metaanalysis on gene expression data from aneuploid cells in diverse organisms, including yeast, plants, mice, and humans. We found highly related gene expression patterns that are conserved between species: genes that were involved in the response to stress were consistently upregulated, and genes associated with the cell cycle and cell proliferation were downregulated in aneuploid cells. Within species, different aneuploidies induced similar changes in gene expression, independent of the specific chromosomal aberrations. Taken together, our results demonstrate that aneuploidies of different chromosomes and in different organisms impact similar cellular pathways and cause a stereotypical antiproliferative response that must be overcome before transformation.stress response | trisomy | chromosomal instability E ukaryotic organisms have evolved elaborate mechanisms that ensure that chromosomes are partitioned equally during cell division (1). Aberrant segregation events can result in aneuploidy, a condition in which cells acquire a karyotype that is not a whole-number multiple of the haploid complement. In humans, aneuploidy is the leading cause of spontaneous abortions and developmental disabilities, and aneuploid karyotypes are observed in greater than 90% of solid tumors (2-4). Thus, understanding the consequences of aneuploidy has broad relevance for the study of mammalian development and cancer.The cause of aneuploidy-induced syndromes remains an open question. For instance, it has been hypothesized that the phenotypes associated with Down syndrome (trisomy 21) are caused by the triplication of a small set of genes that lie within a 5.4-Mb "Down syndrome critical region" on chromosome 21 (5, 6). However, evidence from mouse models suggest that this region is not sufficient to recapitulate Down syndrome-like phenotypes, and genetic mapping of partially trisomic individuals has revealed that numerous regions of chromosome 21 affect clinical presentation (7-9). Alternately, changes in gene dosage across an entire chromosome might have additive effects on organismal development (10). It has been observed that the three human trisomies that survive until birth (trisomy 13, 18, and 21) have the fewest proteincoding genes on them, implying that these karyotypes can be tolerated in utero because they have the lowest net dosage imbalances (11). However, the consequences of copy number variation range from benign to extremely deleterious, demonstrating that different genes exhibit varying levels of dosage sensitivity (12).To examine the consequences of aneuploidy, we have previously constructed and analyzed a series of haploid budding yeast strains and mouse embryonic fibroblasts (MEFs) that carry single extra chromosomes (13-17). These aneuploid cells...

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“…Similar to the Davoli et al study (Davoli et al, 2010), the endoreplication observed in the study by Pampalona et al (Pampalona et al, 2012) requires aberrant (short) telomeres, but also requires loss of the transcriptional repressor Rb, rather than loss of p53. Telomere replication defects also contribute to endoreplication through failed chromosome segregation in mouse embryonic fibroblasts lacking the chromosome cohesion component SA1 (Remeseiro et al, 2012). These telomere studies provide potential mechanistic insight into how some animal tissues respond to DNA damage.…”

Section: Genome Instability Promotes Endoreplicationmentioning

confidence: 99%

Endoreplication and polyploidy: insights into development and disease

2013

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SummaryPolyploid cells have genomes that contain multiples of the typical diploid chromosome number and are found in many different organisms. Studies in a variety of animal and plant developmental systems have revealed evolutionarily conserved mechanisms that control the generation of polyploidy and have recently begun to provide clues to its physiological function. These studies demonstrate that cellular polyploidy plays important roles during normal development and also contributes to human disease, particularly cancer.Key words: Cancer, Endocycle, Endomitosis, Endoreplication, Genome instability IntroductionPolyploid cells, which contain multiples of the diploid genome equivalent, have been studied for many years, nearly as long as chromosomes themselves have been studied. Now, over a century after the discovery of polyploidy, we know much about the molecular mechanisms that generate cellular polyploidy, but comparably little regarding the physiological function of the polyploid state. This discrepancy exists despite the frequent occurrence of polyploid cells in most multicellular organisms, as well as in human cancers. An important aspect of deciphering the roles for polyploidy lies in understanding the regulation of endoreplication, a cell cycle variation that generates a polyploid genome by repeated rounds of DNA replication in the absence of cell division. Recent advances show that, although some differences exist in the diverse endoreplication programs found from protists to humans, core principles can be applied. New work in genetic model organisms has identified cases in which programmed endoreplication plays key roles in development. Furthermore, recent evidence indicates that endoreplication can confer genome instability, a major cancer-enabling property. In this Primer (see Box), we review such recent discoveries, focusing on work carried out in the past 3 years, and refer the reader to other comprehensive reviews on this topic Lee et al., 2009). From these new insights emerge unifying themes regarding endoreplication that hold promise of elucidating the advantages, as well as the potential disadvantages, of polyploidy. Endoreplication and developmentEndoreplication is typically studied in the context of endopolyploidy, which refers to the presence of polyploid cells in an otherwise diploid organism. Diverse levels of polyploidy occur throughout nature (Table 1). Although polyploidy is well appreciated in plants , many different animal tissues, including the skin, gut, placenta, liver, brain and blood have polyploid cells (Table 1) (Laird et al., 1980;Corash et al., 1989;Fox et al., 2010; Hedgecock and White, 1985;Melaragno et al., 1993;Sherman, 1972;Unhavaithaya and Orr-Weaver, 2012;Zanet et al., 2010). Interestingly, endoreplication is not limited to multi-cellular organisms, with examples described in ciliated protozoa (Yin et al., 2010) and even bacteria (Mendell et al., 2008).Two primary forms of endoreplication have been described: endocycling and endomitosis (Fig. 1). Endocycles are compos...

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Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres

Cited by 162 publications

References 69 publications

SA1 binds directly to DNA via its unique AT-hook to promote sister chromatid cohesion at telomeres

SA1 binds directly to DNA via its unique AT-hook to promote sister chromatid cohesion at telomeres

Transcriptional consequences of aneuploidy

Endoreplication and polyploidy: insights into development and disease

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