The INO80 chromatin remodeling complex prevents polyploidy and maintains normal chromatin structure at centromeres

Chambers, A.; Ormerod, Georgina; Durley, Samuel C.; Sing, Tina L.; Brown, Grant W.; Kent, Nicholas A.; Downs, Jessica A.

doi:10.1101/gad.199976.112

Cited by 58 publications

(59 citation statements)

References 40 publications

(56 reference statements)

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“…Our findings identify the Ies2 protein as a potent activator of Ino80 catalytic activity and bring to light an important role for the Ies6 and Arp5 proteins in nucleosome recognition and binding. These observations may provide a mechanistic basis for previous evidence that Ies2, Arp5, and Ies6 contribute to various Ino80-dependent nuclear transactions in fungi and in higher eukaryotes (4,10,(22)(23)(24)(25).…”

Section: Insertion Region Of the Ino80 Snf2-like Atpase Domain Directsmentioning

confidence: 65%

Multiple modes of regulation of the human Ino80 SNF2 ATPase by subunits of the INO80 chromatin-remodeling complex

Chen

Conaway

2013

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

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SNF2 family ATPases are ATP-dependent motors that often function in multisubunit complexes to regulate chromatin structure. Although the central role of SNF2 ATPases in chromatin biology is well established, mechanisms by which their catalytic activities are regulated by additional subunits of chromatin-remodeling complexes are less well understood. Here we present evidence that the human Inositol auxotrophy 80 (Ino80) SNF2 ATPase is subject to regulation at multiple levels in the INO80 chromatin-remodeling complex. The zinc finger histidine triad domain-containing protein Ies2 (Ino Eighty Subunit 2) functions as a potent activator of the intrinsic catalytic activity of the Ino80 ATPase, whereas the YL-1 family Ies6 (Ino Eighty Subunit 6) and actin-related Arp5 proteins function together to promote binding of the Ino80 ATPase to nucleosomes. These findings support the idea that both substrate recognition and the intrinsic catalytic activities of SNF2 ATPases have evolved as important sites for their regulation. Although it is well established that SNF2 family ATPases have evolved to play critical roles as ATPdependent motors that drive many types of chromatin transactions, in most cases how their intrinsic catalytic activities are regulated by their diverse array of associated proteins is poorly understood.The INO80 complex was first identified in Saccharomyces cerevisiae, where it was shown to be composed of roughly 15 subunits (1, 9). Subsequent purification of the human INO80 complex revealed that it shares with its S. cerevisiae counterpart a set of subunits including the Ino80 SNF2 ATPase, the AAA+ ATPases Tip49a and Tip49b, actin-related proteins Arp4, Arp5, and Arp8, and the Ies2 and Ies6 proteins (2, 10-12). The human INO80 complex lacks orthologs of the remaining subunits of the S. cerevisiae INO80 complex and contains instead several apparently metazoan-specific subunits including the deubiquitinating enzyme Uch37, the gene altered in glioma (GLI)-Kruppel family zinc finger transcription factor YY1, the forkhead-associated domain (FHA) containing Mcrs1, nuclear factor related to kB (Nfrkb), and the Amida, Ino80D (FLJ20309), and Ino80E (FLJ90652) proteins.The INO80 complex is capable of regulating chromatin structure in at least two ways. First, it catalyzes ATP-dependent sliding of histone octamers along DNA (1, 2). Second, it catalyzes the replacement of histone H2AZ/histone H2AB dimers in nucleosomes with histone H2A/histone H2B dimers in a reaction that in yeast has been shown to contribute to genome-wide histone H2AZ localization (13).In a recent study dissecting mechanism(s) by which the human INO80 complex catalyzes chromatin remodeling, we found that it is composed of at least three modules that assemble with three distinct domains of the Ino80 protein (14) (Fig. 1A). One module is composed of an Ino80 N-terminal domain and all of the metazoan-specific subunits except YY1. A second, the helicase-SANT-associated (HSA) module, is composed of the Ino80 HSA domain, the actin-related Arp4/Baf53a and ...

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Section: Insertion Region Of the Ino80 Snf2-like Atpase Domain Directsmentioning

confidence: 65%

Multiple modes of regulation of the human Ino80 SNF2 ATPase by subunits of the INO80 chromatin-remodeling complex

Chen

Conaway

2013

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

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“…In addition, evidence suggests that the pericentromeric chromatin adopts a specialized intramolecular structure that is organized by Sgo1 and facilitates biorientation in budding yeast (Yeh et al 2008;Haase et al 2012). Consistent with this, changes in pericentromeric chromatin composition lead to defects in the organization of inner kinetochore proteins and chromosome segregation (Chambers et al 2012;Verdaasdonk et al 2012).…”

mentioning

confidence: 58%

Kinetochore Function and Chromosome Segregation Rely on Critical Residues in Histones H3 and H4 in Budding Yeast

Lenstra²,

Duggan

et al. 2013

Genetics

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Accurate chromosome segregation requires that sister kinetochores biorient and attach to microtubules from opposite poles. Kinetochore biorientation relies on the underlying centromeric chromatin, which provides a platform to assemble the kinetochore and to recruit the regulatory factors that ensure the high fidelity of this process. To identify the centromeric chromatin determinants that contribute to chromosome segregation, we performed two complementary unbiased genetic screens using a library of budding yeast mutants in every residue of histone H3 and H4. In one screen, we identified mutants that lead to increased loss of a nonessential chromosome. In the second screen, we isolated mutants whose viability depends on a key regulator of biorientation, the Aurora B protein kinase. Nine mutants were common to both screens and exhibited kinetochore biorientation defects. Four of the mutants map near the unstructured nucleosome entry site, and their genetic interaction with reduced IPL1 can be suppressed by increasing the dosage of SGO1, a key regulator of biorientation. In addition, the composition of purified kinetochores was altered in six of the mutants. Together, this work identifies previously unknown histone residues involved in chromosome segregation and lays the foundation for future studies on the role of the underlying chromatin structure in chromosome segregation.

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“…A study has suggested that INO80 functions in normal DNA replication in human cells 10 . Consistent with its role in various chromosomal processes, INO80 is critical for the maintenance of genome stability [10][11][12][13] .…”

mentioning

confidence: 94%

Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis

Lee

Lee²,

Hur³

et al. 2014

Nat Commun

103

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The INO80 chromatin-remodelling complex has been implicated in DNA replication during stress in yeast. However, its role in normal DNA replication and its underlying mechanisms remain unclear. Here, we show that INO80 binds to replication forks and promotes fork progression in human cells under unperturbed, normal conditions. We find that Ino80, which encodes the catalytic ATPase of INO80, is essential for mouse embryonic DNA replication and development. Ino80 is recruited to replication forks through interaction with ubiquitinated H2A-aided by BRCA1-associated protein-1 (BAP1), a tumour suppressor and nuclear de-ubiquitinating enzyme that also functions to stabilize Ino80. Importantly, Ino80 is downregulated in BAP1-defective cancer cells due to the lack of an Ino80 stabilization mechanism via BAP1. Our results establish a role for INO80 in normal DNA replication and uncover a mechanism by which this remodeler is targeted to replication forks, suggesting a molecular basis for the tumour-suppressing function of BAP1.

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The INO80 chromatin remodeling complex prevents polyploidy and maintains normal chromatin structure at centromeres

Cited by 58 publications

References 40 publications

Multiple modes of regulation of the human Ino80 SNF2 ATPase by subunits of the INO80 chromatin-remodeling complex

Multiple modes of regulation of the human Ino80 SNF2 ATPase by subunits of the INO80 chromatin-remodeling complex

Kinetochore Function and Chromosome Segregation Rely on Critical Residues in Histones H3 and H4 in Budding Yeast

Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis

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