An acetyltransferase-independent function of Eso1 regulates centromere cohesion

Lin, Su-Jiun; Tapia-Alveal, Claudia; Jabado, Omar; Germain, Doris; O’Connell, Matthew J.

doi:10.1091/mbc.e16-08-0596

Cited by 4 publications

(11 citation statements)

References 48 publications

(88 reference statements)

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“…To this end, cultures were grown at 25°C, and then shifted to the semi-permissive temperature of 30°C for 4 hours. As seen before (Verkade, et al 1999), 30°C has no effect on top2-191 alone (Fig 3A), and the same is true for the eso1 alleles (Lin, et al 2016). All double mutant combinations with top2-191 , however, phenocopied double mutants between top2-191 and Smc5/6 genes (Fig 3A): ∼50% cells with gross mitotic failure characterized by incomplete chromosome segregation and bisection of the nucleus by the division septum.…”

Section: Resultssupporting

confidence: 80%

“…Both double mutant combinations were synthetically lethal at 30°C (Fig 1). As top2-191 potentiates cohesin retention, this was a somewhat unexpected result, as these eso1 alleles are predicted to lower the overall level of sister chromatid cohesion, and indeed eso1-H17 suppresses the cohesin-retention defects of smc6-74 (Lin, et al 2016). …”

Section: Resultsmentioning

confidence: 91%

“…We therefore investigated functional interactions between top2-191 and two alleles of eso1 : the ts lethal eso1-H17 allele (Tanaka, et al 2000), which has undetectable Psm3 acetylation at all temperatures (Feytout, et al 2011, Lin, et al 2016), and the non-ts allele eso1-1 , that is severely compromised, though not ablated for Psm3 acetylation (Lin, et al 2016). Both double mutant combinations were synthetically lethal at 30°C (Fig 1).…”

Section: Resultsmentioning

confidence: 99%

“…As activation of the spindle checkpoint dictates the lethality of eso1-H17 (but not eso1-1 ) at 36°C (Lin, et al 2016), we next investigated whether this could be a source of synthetic lethality. In no case did short spindles accumulate (not shown).…”

Section: Resultsmentioning

confidence: 99%

“…In this context, Eso1 dysfunction is not related to cohesin acetylation or recruitment, but does result in a failure of centromeric cohesion. Interestingly, smc6-74 eso1-H17 double mutants co-suppress: smc6-74 suppresses the premature centromere separation seen in eso1-H17 , while eso1-H17 suppresses the retention of cohesin on chromosome arms seen in smc6-74 (Lin, et al 2016). …”

Section: Introductionmentioning

confidence: 99%

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DNA Topoisomerase II modulates acetyl-regulation of cohesin-mediated chromosome dynamics

Lin

O’Connell

2017

Curr Genet

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Cohesin is one of three multi-protein Structural Maintenance of Chromosomes (SMC) complexes that regulate eukaryotic chromosome dynamics. It forms a ring-shaped structure that embraces sister chromatids through interphase to promote their pairing. In preparation for mitosis, most cohesin is stripped from the chromosome arms in prophase by a poorly defined process that is associated with cohesin phosphorylation. In the fission yeast Schizosaccharomyces pombe this prophase pathway is dependent on the cohesin-related Smc5/6 complex, and this requirement is heightened in Smc5/6 hypomorphs by DNA damage, replication stress and Topoisomerase II (Top2) dysfunction. Cohesin interacts with chromosomes immediately upon mitotic exit, and becomes cohesive coincident with DNA replication. Cohesiveness is promoted by acetylation of the Smc3 subunit by an acetyltransferase, known as Eso1 in the S. pombe, which counteracts the anti-cohesive function(s) of the cohesin regulators Pds5 and Wpl1. We recently showed that Eso1 and Smc5/6 antagonize each other, and concurrent inactivation restores sister chromatid separation following genotoxic stress. Here, we have investigated the relationship between Top2 and Eso1 in successful completion of mitosis. We observe that partial inactivation of both results in a synthetic lethal mitotic block, but this is not overcome by deleting pds5 or wpl1. However, analysis of both acetyl-blocking and mimetic mutations in Smc3 indicates that the cycling of cohesin acetyl-regulation is more important than acetyl-status per se, highlighting the non-linear nature of the cohesin cycle.

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNA Topoisomerase II modulates acetyl-regulation of cohesin-mediated chromosome dynamics

Lin

O’Connell

2017

Curr Genet

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Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

et al. 2022

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Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.

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Biology and physics of heterochromatin-likedomains/complexes

Singh

Belyakin

Laktionov

2020

Preprint

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The hallmarks of constitutive heterochromatin, HP1 and H3K9me2/3, assemble heterochromatin-like domains/complexes outside canonical constitutively heterochromatic territories where they regulate chromatin-templated processes. Domains are more than 100kb in size; complexes less than 100kb. They are present in the genomes of organisms ranging from fission yeast to man, with an expansion in size and number in mammals. Some of the likely functions of the domains/complexes include silencing of the donor mating type region in fission yeast, regulation of mammalian imprinted genes and the phylotypic progression during vertebrate development. Far cis- and trans-contacts between micro-phase separated domains/complexes in mammalian nuclei contribute to the emergence of epigenetic compartmental domains (ECDs) detected in Hi-C maps. We speculate that a thermodynamic description of micro-phase separation of heterochromatin-like domains/complexes will require a gestalt shift away from the monomer as the unit-of-incompatibility, where it is the choice of monomer that determines the sign and magnitude of the Flory-Huggins parameter, χ. Instead, a more dynamic structure, the oligo-nucleosomal 'clutch', consisting of between 2 to 10 nucleosomes is both the long sought-after secondary structure of chromatin and its unit of incompatibility. Based on this assumption we present a simple theoretical framework that enables an estimation of χ for domains/complexes flanked by euchromatin and thereby an indication of their tendency to phase separate. The degree of phase separation is specified by χN, where N is the number of 'clutches' in a domain/complex. Our approach may provide an additional tool for understanding the biophysics of the 3D genome.

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An acetyltransferase-independent function of Eso1 regulates centromere cohesion

Abstract: The lethality of eso1 mutants is due to activation of the spindle assembly checkpoint and is triggered by premature centromere separation. This novel role for Eso1 at the centromeres is independent of Smc3 acetylation, and the defect arises in an Smc5/6-dependent manner.

Cited by 4 publications

References 48 publications

DNA Topoisomerase II modulates acetyl-regulation of cohesin-mediated chromosome dynamics

DNA Topoisomerase II modulates acetyl-regulation of cohesin-mediated chromosome dynamics

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Biology and physics of heterochromatin-likedomains/complexes

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