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Review
. 2009 Jun;10(6):373-84.
doi: 10.1038/nrm2693. Epub 2009 May 8.

Chromatin remodelling beyond transcription: the INO80 and SWR1 complexes

Ashby J Morrison  1 , Xuetong Shen
Affiliations
Review

Chromatin remodelling beyond transcription: the INO80 and SWR1 complexes

Ashby J Morrison et al. Nat Rev Mol Cell Biol. 2009 Jun.

Abstract

Chromatin-modifying factors have essential roles in DNA processing pathways that dictate cellular functions. The ability of chromatin modifiers, including the INO80 and SWR1 chromatin-remodelling complexes, to regulate transcriptional processes is well established. However, recent studies reveal that the INO80 and SWR1 complexes have crucial functions in many other essential processes, including DNA repair, checkpoint regulation, DNA replication, telomere maintenance and chromosome segregation. During these diverse nuclear processes, the INO80 and SWR1 complexes function cooperatively with their histone substrates, gamma-H2AX and H2AZ. This research reveals that INO80 and SWR1 ATP-dependent chromatin remodelling is an integral component of pathways that maintain genomic integrity VSports手机版. .

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Figures

Figure 1 |
Figure 1 |. Chromatin-remodelling mechanisms of the INO80 and SWR1 complexes.
| a | Phylogeny of Saccharomyces cerevisiae chromatin-remodelling ATPase subunits. Members of the ISWI, SWI/SNF, CHD1 and INO80 subfamilies are shown. b | ATPase subunits of the INO80 and SWI/SNF subfamilies are shown. The ATPase domain of the INO80 subfamily is split in the middle by a spacer region. The SWI/SNF ATPase subunit contains a bromodomain (Bromo), which binds to acetylated histones. Both subunits contain a helicase-SANT-associated (HSA) domain that mediates the association of the subunit with actin and actin-related proteins (Arps). c | Distinct ATP-dependent chromatinremodelling mechanisms of INO80 and SWR1 complexes. The INO80 complex repositions nucleosomes to a central position from the end of the DNA. The SWR1 complex incorporates the histone variant Htz1 into the nucleosome. Both mechanisms require ATP hydrolysis and the function of actin and Arp subunits in the complexes.
Figure 2 |
Figure 2 |. INO80 and SWR1 complexes regulate double-strand break repair.
The Saccharomyces cerevisiae kinases Tel1 and Mec1 (ataxia telangiectasia (A-T) mutated (ATM) and A-T and RAD3-related (ATR) in mammals) phosphorylate H2AX after the creation of a double-strand break, which can be repaired by homologous recombination (HR) or non-homologous end joining (NHEJ). During HR and NHEJ, the INO80 and SWR1 complexes bind to phosphorylated H2AX. The INO80 complex is involved in nucleosome eviction proximal to the break site. The DNA ends are then recognized by the Mre11–Rad50–Xrs2 (MRX) complex. The Mre11 nuclease is involvedin the production of single-stranded DNA. During HR, the single-stranded DNA-binding protein replication protein A (RPA) and the Mec1 checkpoint kinase bind to resected DNA. The cohesin complex assists in holding the sister chromatids together,. The Rad52 epistasis group, which includes Rad51, Rad52 and Rad54, facilitate the search for and synapsis of homologous DNA sequences. A Holliday junction is formed between the two DNA strands, followed by DNA synthesis and resolution of the junction. During NHEJ, the SWR1 complex promotes the association of Ku80 to the DNA ends, a component of the Ku70–Ku80 complex that is required for NHEJ. Repair is then completed following ligation of the DNA ends. Mutants of the INO80 complex have defects in HR and NHEJ, whereas mutants of the SWR1 complex have defects in error-free NHEJ.
Figure 3 |
Figure 3 |. The INO80 complex is a component of the Tel1 and Mec1 pathway.
Following the creation of a double-strand break, the Saccharomyces cerevisiae kinases Tel1 and Mec1 (ataxia telangiectasia (A-T) mutated (ATM) and A-T and RAD3-related (ATR) in mammals) phosphorylate H2AX. The non-histone protein 10 (Nhp10) subunit of the INO80 complex is needed for the complex to associate with phosphorylated H2AX (γ-H2AX). Once localized to the DNA break site, core catalytic subunits, such as actin-related protein 5 (Arp5) and Arp8, participate in DNA repair processes. The Tel1 and Mec1 kinases also phosphorylate INO80 subunit 4 (Ies4) to regulate the cell cycle checkpoint response. Therefore, Tel1 and Mec1 regulate two aspects of the INO80 complex when cells are exposed to DNA-damaging agents: the phosphorylation of H2AX, leading to the recruitment of the INO80 complex at DNA damage sites, and phosphorylation of the Ies4 subunit to influence the cell cycle checkpoint response.
Figure 4 |
Figure 4 |. The INO80 complex promotes recovery of stalled replication forks.
During replication, DNA synthesis is catalysed by the replisome, which contains polymerases, primases and helicases. Histone chaperones deposit histones on to newly synthesized DNA. Replication forks stall when exposed to replication stress, such as depleted dNTP pools. When this happens, the replisome is stabilized by DNA damage response factors, such as the Saccharomyces cerevisiae INO80 complex and the Tof1 and Mrc1 checkpoint factors, which activate the intra-S phase checkpoint to prevent replication origin firing. On the removal of replication stress, the replication fork recovers and DNA synthesis resumes. In the absence of the INO80 complex, fork stability defects occur as the replisome is destabilized and some of its components dissociate, leaving others, such as proliferating cell nuclear antigen (PCNA), at the replication fork. In this case, replication does not restart following the removal of replication stress. Accordingly, checkpoint recovery is delayed and DNA damage accumulates.
Figure 5 |
Figure 5 |. Regulation of aTP-dependent chromatin remodelling.
Seven distinct mechanisms in combination can generate numerous structural and functional diversities for a single chromatin-remodelling complex. Transcription factors can target the complex for recruitment to specific target genes. The binding of structured DNA, such as three-way and four-way junctions that represent DNA replication and repair intermediates, can also recruit and potentially alter the activity of the complex. Small molecules, such as inositol polyphosphates and phosphoinositides, can modulate the activity of the complex. Additionally, subunits in the complex can be post-translationally modified or exchanged (swapped) to alter the function of the complex. The activity of specific subunits can also be regulated by transient association of the complex with activating factors, such as the activation of the deubiquitylating enzyme ubiquitin carboxy-terminal hydrolase 37 (UCH37) following association of this 19S proteasome component to the INO80 complex. Finally, the association of unique chromatin substrates, such as histone variants and post-translationally modified histones, can further specify the chromatin-remodelling mechanisms of the complex.
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