Sister DNA Entrapment between Juxtaposed Smc Heads and Kleisin of the Cohesin Complex

Chapard, Christophe; Jones, Robert C.; Oepen, Till van; Scheinost, Johanna C.; Nasmyth, K

doi:10.1016/j.molcel.2019.05.023

Cited by 70 publications

(91 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ATP binding induces changes in the mutual positions (and conformations) of the SMC heads and arms 10,27,[46][47][48] . Consequently, the shape of the whole SMC complex changes from a rod-like conformation (with juxtaposed arms stabilized by their mutual interactions) to the less stable open ring (Fig.…”

Section: Discussionmentioning

confidence: 99%

A role of the Nse4 kleisin and Nse1/Nse3 KITE subunits in the ATPase cycle of SMC5/6

Vondrová

Kolesar

Adamus

et al. 2020

Sci Rep

View full text Add to dashboard Cite

The SMC (Structural Maintenance of Chromosomes) complexes are composed of SMC dimers, kleisin and kleisin-interacting (HAWK or KITE) subunits. Mutual interactions of these subunits constitute the basal architecture of the SMC complexes. In addition, binding of ATP molecules to the SMC subunits and their hydrolysis drive dynamics of these complexes. Here, we developed new systems to follow the interactions between SMC5/6 subunits and the relative stability of the complex. First, we show that the N-terminal domain of the Nse4 kleisin molecule binds to the SMC6 neck and bridges it to the SMC5 head. Second, binding of the Nse1 and Nse3 KITE proteins to the Nse4 linker increased stability of the ATP-free SMC5/6 complex. In contrast, binding of ATP to SMC5/6 containing KITE subunits significantly decreased its stability. Elongation of the Nse4 linker partially suppressed instability of the ATP-bound complex, suggesting that the binding of the KITE proteins to the Nse4 linker constrains its limited size. Our data suggest that the KITE proteins may shape the Nse4 linker to fit the ATP-free complex optimally and to facilitate opening of the complex upon ATP binding. This mechanism suggests an important role of the KITE subunits in the dynamics of the SMC5/6 complexes.

show abstract

Section: Discussionmentioning

confidence: 99%

A role of the Nse4 kleisin and Nse1/Nse3 KITE subunits in the ATPase cycle of SMC5/6

Vondrová

Kolesar

Adamus

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The protein complex condensin has been shown to be both necessary and sufficient for mitotic chromosome compaction [8][9][10][11][12][13][14], but the molecular mechanism by which it performs this task remains unknown. It has been hypothesized [15][16][17] that condensin and other SMC (structural maintenance of chromosomes) complexes are molecular motors that actively extrude chromatin loops through a yet to be discovered mechanism [18,19]. These loop-extruding factors (LEFs) load onto the chromatin fiber and progressively form larger loops by reeling chromatin into the loops [ Fig.…”

mentioning

confidence: 99%

“…3(a), right]. Equation (19) indicates that a fast, but physiologically plausible, switching rate is required to achieve robust compaction. For example, F C ¼ 100 requires k s =k u ¼ 2.9, while F C ¼ 1000 requires k s =k u ¼ 10.8.…”

mentioning

confidence: 99%

Limits of Chromosome Compaction by Loop-Extruding Motors

Banigan

Mirny

2019

Phys. Rev. X

View full text Add to dashboard Cite

During mitosis, human chromosomes are linearly compacted about 1000-fold by loop-extruding motors. Recent experiments have shown that condensins extrude DNA loops but in a "one-sided" manner. This contrasts with existing models, which predict that symmetric, "two-sided" loop extrusion accounts for mitotic chromosome compaction. We explore whether one-sided extrusion, as it is currently seen in experiments, can compact chromosomes by developing a mean-field theoretical model for polymer compaction by motors that actively extrude loops and dynamically turnover. The model establishes a stringent upper bound of only about tenfold for compaction by strictly one-sided extrusion. We confirm this result with stochastic simulations. Thus, strictly one-sided extrusion as it has been observed so far cannot be the sole mechanism of chromosome compaction. However, as shown by the model, other two-sided or effectively two-sided mechanisms can achieve sufficient compaction.

show abstract

“…The negative charges bring about by phosphorylated residues may also hinder or modify cohesin interaction with DNA. A recent study indicates that cohesin would tether DNA in its smaller lumen that is, between Rad21 and the SMC's heads [60]. The two acetylatable lysine residues within Psm3 head domain are thought to stimulate the ATPase activity of cohesin when in contact with DNA [20].…”

Section: Discussionmentioning

confidence: 99%

The CDK Pef1 and Protein Phosphatase 4 oppose each other for regulating cohesin binding to fission yeast chromosomes

Birot

Tormos-Pérez

Vaur

et al. 2019

Preprint

View full text Add to dashboard Cite

Cohesin has essential roles in chromosome structure, segregation and repair. Cohesin binding to chromosomes is catalyzed by the cohesin loader, Mis4 in fission yeast. How cells fine tune cohesin deposition is largely unknown. Here we provide evidence that Mis4 activity is regulated by phosphorylation of its cohesin substrate. A genetic screen for negative regulators of Mis4 yielded a CDK called Pef1, whose closest human homologue is CDK5. Inhibition of Pef1 kinase activity rescued cohesin loader deficiencies. In an otherwise wildtype background, Pef1 ablation stimulated cohesin binding to its regular sites along chromosomes while ablating Protein Phosphatase 4 had the opposite effect. Pef1 and PP4 control the phosphorylation state of the cohesin kleisin Rad21. The CDK phosphorylates Rad21 on Threonine 262. Pef1 ablation, non phosphorylatable Rad21-T262 or mutations within a Rad21 binding domain of Mis4 alleviated the effect of PP4 deficiency. Such a CDK/PP4 based regulation of cohesin loader activity could provide an efficient mechanism for translating cellular cues into a fast and accurate cohesin response.3 DNA capture may be achieved by modulating the catalytic activity of the loader and concerted transcriptional responses may involve a local and temporal control of loading and unloading activities. How cells orchestrate cohesin functions is largely unknown. Intriguingly, the kleisin subunit of cohesin is targeted by multiple phosphorylation events. In fission yeast, Rad21 shows multiple phospho-isoforms whose relative abundance fluctuates along the cell cycle [39]. Our recent work showed that Protein Phosphatase 4 (PP4) controls the phosphorylation status of Rad21 and modulates Wpl1 activity [40], leading to the idea that cohesin functions could be spatially and temporally fine-tuned by altering the balance between kinase and phosphatase activities.Here we report on the control of cohesin deposition by the opposite activities of the Pef1 CDK and PP4. Pef1 was first described as a PSTAIRE-related protein in fission yeast [41]. The CDK has three known cyclin partners called Pas1, Psl1 and Clg1 and was reported to facilitate the G1 to S phase transition and to regulate life span [42; 43]. Its closest human homolog, CDK5, is involved in a myriad of cellular functions and pathologies, from neurodegenerative diseases to multiple solid and hematological cancers [44]. We identified pef1 in a genetic screen for mutants able to rescue the cohesin loader mutant mis4-367. Pef1 ablation or inhibition of its kinase activity increased cohesin deposition and rescued sister-chromatid cohesion defects of the mis4 mutant. In otherwise wild-type cells Pef1 ablation increased the binding of both cohesin and its loader to their regular sites along chromosomes. Genetic analyses indicated that Pef1 acts through the phosphorylation of multiple targets. We identified one of these within the kleisin Rad21. Specifically, the Pef1/Psl1 complex phosphorylates Rad21 on T262 and preventing this phosphorylation event recapitulates in part th...

show abstract

Sister DNA Entrapment between Juxtaposed Smc Heads and Kleisin of the Cohesin Complex

Cited by 70 publications

References 60 publications

A role of the Nse4 kleisin and Nse1/Nse3 KITE subunits in the ATPase cycle of SMC5/6

A role of the Nse4 kleisin and Nse1/Nse3 KITE subunits in the ATPase cycle of SMC5/6

Limits of Chromosome Compaction by Loop-Extruding Motors

The CDK Pef1 and Protein Phosphatase 4 oppose each other for regulating cohesin binding to fission yeast chromosomes

Contact Info

Product

Resources

About