The INO80 remodeller in transcription, replication and repair

Abstract

The accessibility of eukaryotic genomes to the action of enzymes involved in transcription, replication and repair is maintained despite the organization of DNA into nucleosomes. This access is often regulated by the action of ATP-dependent nucleosome remodellers. The INO80 class of nucleosome remodellers has unique structural features and it is implicated in a diverse array of functions, including transcriptional regulation, DNA replication and DNA repair. Underlying these diverse functions is the catalytic activity of the main ATPase subunit, which in the context of a multisubunit complex can shift nucleosomes and carry out histone dimer exchange. studies showed that INO80 promotes replication fork progression on a chromatin template, while it was shown to facilitate replication fork restart after stalling and to help evict RNA polymerase II at transcribed genes following the collision of a replication fork with transcription. More recent work in yeast implicates INO80 in the general eviction and degradation of nucleosomes following high doses of oxidative DNA damage. Beyond these replication and repair functions, INO80 was shown to repress inappropriate transcription at promoters in the opposite direction to the coding sequence. Here we discuss the ways in which INO80's diverse functions help maintain genome integrity.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.

Somatic Genetic Aberrations in Benign Breast Disease and the Risk of Subsequent Breast Cancer

“…INO80D is one of 13 subunits of the ATP-dependent chromatin remodeling complex INO80 58 . INO80 exhibits a plethora of functions including transcriptional regulation, DNA replication and repair 59 . Mammalian INO80 stabilizes stalled replication forks and enables their restart following release from replication arrest and therefore, not surprisingly, INO80deficient cells evidence decreased fork stability, fork collapse and formation of double-strand breaks in response to replication stress 58 .…”

Hap2-Ino80 facilitated transcription promotesde novoestablishment of CENP-A chromatin

“…The conserved heptad repeat composing the C-terminal domain (CTD) of RNAPII undergoes S5 phosphorylation (S5P) at promoters upon transcription initiation and S2 phosphorylation (S2P) in coding regions during transcriptional elongation (Komarnitsky et al, 2000). RNAPII stalls when it encounters obstacles such as DNA damage or natural barriers (Poli et al, 2017). Despite relatively high levels of RNAPII being detected on H3-assembled ectopic central domain, meagre levels of transcripts are produced, consistent with transcriptional stalling (Catania et al, 2015;Choi et al, 2011).…”

The INO80 ATP-dependent chromatin remodelling complex alleviates stalled Polymerase II to promote non-coding RNA transcription termination

“…disease (Poli et al, 2017;Zhang et al, 2017a;Zhou et al, 2016). It is therefore anticipated that our reported chromatin mechanism of co-transcriptional RNA quality control has general relevance for regulation of eukaryotic gene expression and in disease.…”

“…The multisubunit ATP-dependent chromatin remodelling complex INO80 has a wellestablished and important role in transcription regulation of protein-coding genes across eukaryotes (Poli et al, 2017). INO80 is enriched at the transcription start sites (TSS) of the majority of active and poised mRNA genes in yeast and mammals (Xue et al, 2017;Yen et al, 2013).…”

“…INO80 is enriched at the transcription start sites (TSS) of the majority of active and poised mRNA genes in yeast and mammals (Xue et al, 2017;Yen et al, 2013). The nucleosome remodelling activity of INO80 exchanges the histone variant H2A.Z for H2A in nucleosomes and alters nucleosome positions (Poli et al, 2017). While it is generally proposed that the function of INO80 during transcription is to control transcription initiation, the mechanism through which INO80 regulates transcription is not well characterized.…”