Interplay between Ino80 and Swr1 chromatin remodeling enzymes regulates cell cycle checkpoint adaptationin response to DNA damage

Papamichos‐Chronakis, Manolis; Krebs, Jocelyn E.; Peterson, Craig L.

doi:10.1101/gad.1440206

Cited by 182 publications

(181 citation statements)

References 46 publications

(85 reference statements)

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“…yINO80 has also been shown to induce γ-H2AX following exposure to DNA-damaging agents and to modulate downstream DNA damage checkpoint functions [26,58]. We found that both γ-H2AX and 53BP1 efficiently localized to IR-induced DSBs and to dysfunctional telomeres in mIno80 ∆/∆ MEFs, suggesting that mIno80 is not required for the accumulation of γ-H2AX and 53BP1 at DNA damage sites.…”

Section: Discussionmentioning

confidence: 74%

The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

et al. 2013

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The INO80 (inositol requiring mutant 80) chromatin remodeling complex plays important roles in transcriptional regulation and DNA replication and repair, and consists of several functional protein subunits, including the critical Ino80 ATPase catalytic subunit. While the function of INO80 has been studied in yeast and mammalian cell lines, we do not know how mIno80 contributes to the maintenance of genome stability to prevent cancer development in mice. Here, we use a conditional knockout approach to explore the cellular and organismal functions of mIno80. Deletion of mIno80 results in profound cellular proliferative defects and activation of p21-dependent cellular senescence. While mIno80 is required for efficient repair of DNA double strand breaks, its depletion did not impact upon the formation of γ-H2AX and 53BP1 DNA damage foci, or the activation of the ATM-CHK2-dependent DNA damage response. mIno80 deletion inhibited the generation of single-strand DNA, resulting in defects in homology-directed DNA repair (HDR) at telomeres. Fragile telomeres were prominent in mIno80 ∆/∆ MEFs, suggesting that chromatin remodeling is required for efficient telomere replication. mIno80 −/− mouse embryos die early during embryogenesis, while conditional deletion of mIno80 in adult mice results in weight loss and premature death. In a p53 −/− tumorprone background, mIno80 haploinsufficiency favored the development of sarcomas. Our studies suggest that the mIno80 chromatin remodeling complex plays important roles in telomere replication, HDR-mediated repair of dysfunctional telomeres, and maintenance of genome stability.

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Section: Discussionmentioning

confidence: 74%

The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

et al. 2013

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“…Perhaps the most specialized function of remodelers involves histone-variant exchange. Only SWR1 efficiently replaces H2A-H2B dimers with Htz1-H2B dimers in vitro 19 , and new in vivo evidence supports a role for the INO80 remodeler in the reverse reaction, which may be important for recovery from DNA repair 26 .…”

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confidence: 86%

Chromatin remodeling: insights and intrigue from single-molecule studies

Cairns

2007

Nat Struct Mol Biol

227

208

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Chromatin remodelers are ATP-hydrolyzing machines specialized to restructure, mobilize or eject nucleosomes, allowing regulated exposure of DNA in chromatin. Recently, remodelers have been analyzed using single-molecule techniques in real time, revealing them to be complex DNA-pumping machines. The results both support and challenge aspects of current models of remodeling, supporting the idea that the remodeler translocates or pumps DNA loops into and around the nucleosome, while also challenging earlier concepts about loop formation, the character of the loop and how it propagates. Several complex behaviors were observed, such as reverse translocation and long translocation bursts of the remodeler, without appreciable DNA twist. This review presents and discusses revised models for nucleosome sliding and ejection that integrate this new information with the earlier biochemical studies.Many processes involving chromosomes are guided by DNA-binding proteins, and the access of these proteins to DNA is regulated by chromatin. Nucleosomes, the primary repeating unit of chromatin, package DNA by wrapping 147 base pairs (bp) around an octamer of histone proteins in ∼1.7 helical turns 1-3 . This packaging provides topological order but occludes one face of the DNA, which slows or prevents the recognition of DNA sequences by DNA-binding proteins. To maintain topological order, and also to allow rapid and regulated access to the DNA, cells have evolved a set of chromatin-remodeling machines that alter nucleosome position, presence and structure.Remodelers can be separated into several families on the basis of their composition and activities: SWI/SNF, ISWI, NURD/Mi-2/CHD and the 'split ATPases' INO80 and SWR1 (which bear an insertion within their ATPase domains). Rad54 may represent an additional family, as it perturbs chromatin in vitro, but it apparently lacks specific nucleosome-interacting domains 4,5 . The participation of remodelers in various chromosomal processes has been the subject of many reviews 6-9 . The present work focuses solely on remodeler mechanisms, and primarily on the function of their conserved catalytic subunit, a superfamily 2 (SF2) ATPdependent DNA translocase. Recently, single-molecule approaches have been used to examine several remodelers, providing many new insights into their behavior. Here I discuss these recent studies, compare them with previous biochemical studies and suggest refinements to existing models to account for some of the observations. Remodelers slide, eject and restructure nucleosomesRemodelers can affect nucleosomes in at least four ways ( Fig. 1): (i) sliding, or moving the histone octamer to a new position, which exposes DNA 10-12 ; (ii) ejection, or completely displacing the octamer to expose DNA [13][14][15][16] ; (iii) removal of H2A-H2B dimers, leaving only the central H3-H4 tetramer, which exposes DNA and destabilizes the nucleosome 17,18 ; and (iv) dimer replacement-for example, exchanging the resident H2A-H2B dimers for dimers NIH Public Access

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“…A possible other substrate of Cdc5 in the adaptation response is the Ino80 chromatin remodeling complex (Papamichos-Chronakis et al 2006). Loss of Ino80 activity in yeast cells cause aberrant incorporation of histone H2AZ variant in chromatin proximal to DSBs and is associated with an inability to adapt to DNA damage.…”

Section: Polo-like Kinasesmentioning

confidence: 99%

“…It is believed that Ino80 acts by maintaining high levels of phosphorylated histone H2AX in damaged cells. In the absence of Ino80 complex, another chromatin remodeling factor replaces phospho-H2AX with H2AZ, thereby limiting checkpoint activation (Papamichos-Chronakis et al 2006). It will be interesting to determine whether Ino80 complex components are substrates for Cdc5 during the cell cycle or in response to DNA damage.…”

Section: Polo-like Kinasesmentioning

confidence: 99%

When genome integrity and cell cycle decisions collide: roles of polo kinases in cellular adaptation to DNA damage

Serrano

D’Amours

2014

Syst Synth Biol

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The drive to proliferate and the need to maintain genome integrity are two of the most powerful forces acting on biological systems. When these forces enter in conflict, such as in the case of cells experiencing DNA damage, feedback mechanisms are activated to ensure that cellular proliferation is stopped and no further damage is introduced while cells repair their chromosomal lesions. In this circumstance, the DNA damage response dominates over the biological drive to proliferate, and may even result in programmed cell death if the damage cannot be repaired efficiently. Interestingly, the drive to proliferate can under specific conditions overcome the DNA damage response and lead to a reactivation of the proliferative program in checkpoint-arrested cells. This phenomenon is known as adaptation to DNA damage and is observed in all eukaryotic species where the process has been studied, including normal and cancer cells in humans. Polo-like kinases (PLKs) are critical regulators of the adaptation response to DNA damage and they play key roles at the interface of cell cycle and checkpoint-related decisions in cells. Here, we review recent progress in defining the specific roles of PLKs in the adaptation process and how this conserved family of eukaryotic kinases can integrate the fundamental need to preserve genomic integrity with effective cellular proliferation.

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Interplay between Ino80 and Swr1 chromatin remodeling enzymes regulates cell cycle checkpoint adaptationin response to DNA damage

Abstract: Supplemental material is available at http://www.genesdev.org.

Cited by 182 publications

References 46 publications

The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

Chromatin remodeling: insights and intrigue from single-molecule studies

When genome integrity and cell cycle decisions collide: roles of polo kinases in cellular adaptation to DNA damage

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