Mouse Rif1 is a regulatory subunit of protein phosphatase 1 (PP1)

Sukackaitė, Rasa; Cornacchia, Daniela; Jensen, Malene Ringkjøbing; Mas, Philippe J.; Blackledge, Martin; Enervald, Elin; Duan, Guangyou; Auchynnikava, Tania; Köhn, Maja; Hart, Darren J.; Buonomo, Sara B.C.

doi:10.1038/s41598-017-01910-1

Cited by 50 publications

(47 citation statements)

References 55 publications

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“…To further understand these mechanistic differences, we assessed what role the PP1 binding motif within Rif1 has on RT control of pericentric heterochromatin in wing discs and follicle cells. Rif1 orthologs from yeasts to humans contain a PP1 binding motif, and mutation of this motif prevents Rif1 association with PP1 in multiple systems ((Davé et al 2014; Hiraga et al 2014; Mattarocci et al 2014; Sreesankar et al 2015; Alver et al 2017; Hiraga et al 2017; Sukackaite et al 2017)). We previously generated an allele of Rif1 ( Rif1 PP1 ) where the conserved SILK/RSVF PP1 interaction motif is mutated to SAAK/RASA (Munden et al 2018).…”

Section: Resultsmentioning

confidence: 99%

“…Although Rif1 is only modestly conserved, all Rif1 orthologs contain a P rotein P hosphatase 1 (PP1)-interaction motif, suggesting that PP1 recruitment is a critical function of Rif1. Rif1-dependent recruitment of PP1 to chromatin may prevent the Dbf4-dependent kinase (DDK) activation of loaded helicases (Davé et al 2014; Hiraga et al 2014; Mattarocci et al 2014; Hiraga et al 2017; Sukackaite et al 2017). How loss of the Rif1-PP1 interaction affects RT genome wide, however, has not been determined.…”

Section: Introductionmentioning

confidence: 99%

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Rif1 functions in a tissue-specific manner to control replication timing through its PP1-binding motif

Armstrong¹,

Das

Hill³

et al. 2019

Preprint

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22Replication initiation in eukaryotic cells occurs asynchronously throughout S phase, yielding early 23 and late replicating regions of the genome, a process known as replication timing (RT). RT changes 24 during development to ensure accurate genome duplication and maintain genome stability. To 25 understand the relative contributions that cell lineage, cell cycle, and replication initiation 26 regulators have on RT, we utilized the powerful developmental systems available in Drosophila 27 melanogaster. We generated and compared RT profiles from mitotic cells of different tissues and 28 from mitotic and endocycling cells of the same tissue. Our results demonstrate that cell lineage has 29 the largest effect on RT, whereas switching from a mitotic to an endoreplicative cell cycle has little 30 to no effect on RT. Additionally, we demonstrate that the RT differences we observed in all cases 31 are largely independent of transcriptional differences. We also employed a genetic approach in 32 these same cell types to understand the relative contribution the eukaryotic RT control factor, Rif1, 33 has on RT control. Our results demonstrate that Rif1 can function in a tissue-specific manner to 34 control RT. Importantly, the Protein Phosphatase 1 (PP1) binding motif of Rif1 is essential for 35 Rif1 to regulate RT. Together, our data support a model in which the RT program is primarily 36 driven by cell lineage and is further refined by Rif1/PP1 to ultimately generate tissue-specific RT 37 programs. 38

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rif1 functions in a tissue-specific manner to control replication timing through its PP1-binding motif

Armstrong¹,

Das

Hill³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…We have recently identified the sites within RIF1 that mediate the physical contacts with PP1 (SILK and RVSF motifs, residues 2128-2131 and 2150-2153). Point mutations of these residues reduce PP1 interaction to undetectable levels (RIF1 DPP1 : SILK into SAAA and RVSF into RVSA, 52 ). We therefore sought to express the Rif1 DPP1 mutant in mESCs.…”

Section: Mouse Embryonic Stem Cells Expressing Rif1 Dpp1mentioning

confidence: 99%

“…For example, RIF1-DPP1 may only specifically interfere with the PP1-dependent control of DDK (Dbf4dependent kinases) activity at origins, while other RIF1 interactors may contribute to the epigenetic control of origin activation. The proteins associated with RIF1 are enriched for chromatin and epigenetic regulators 52 , and the contribution of histone modifiers to the control of replication timing has long been recognised [58][59][60][61][62][63] . However, an understanding of the effect of Rif1 deletion on the epigenetic landscape is still missing, leaving this hypothesis currently hard to test 12,13,38,64 .…”

Section: Rif1 Dosage Is Important For Nuclear Compartmentalisationmentioning

confidence: 99%

Nuclear organisation and replication timing are coupled through RIF1-PP1 interaction

Gnan

Flyamer

Klein

et al. 2019

Preprint

Self Cite

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Parallels between three-dimensional genome organisation and replication timing suggests the hypothesis of their possible interdependence. However, it remains unknown whether nuclear architecture overall plays an instructive role in the replication-timing program. Here we demonstrate that they are coupled through RIF1, the molecular hub that co-regulates both processes. Both nuclear organisation and replication timing depend upon the interaction between RIF1 and PP1. However, whereas nuclear architecture requires the full complement of RIF1 and its interaction with PP1, replication timing is not sensitive to RIF1 dosage. RIF1's role in replication timing also extends beyond its interaction with PP1. Availing of this separation-of-function approach, we have therefore identified the molecular bases of the co-dependency of the replication-timing program and nuclear architecture.

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“…In DNA replication control, Rif1 counteracts the function of DDK by directing Protein Phosphatase 1 (PP1) to dephosphorylate MCM proteins and oppose replication initiation. Notably, this action of Rif1 as a substrate-targeting subunit for PP1 is evolutionarily conserved, with Rif1 also controlling replication initiation in mammalian cells [8][9][10][21][22][23]. Budding yeast Rif1 and PP1 bound to the chromosome ends specify the late replication timing of origins in the vicinity of telomeres [8,10,[24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Budding yeast Rif1 binds to replication origins and protects DNA at blocked replication forks

et al. 2019

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It came to the authors' attention that in the original paper, an incorrect conversion factor was used for the pixel to micrometre conversion when analysing microscope images of combed fibres. The conversion factor used was 7.2 pixels = 1 lm instead of 13.9 pixels = 1 lm.The authors have re-analysed the affected data with the correct conversion factor of 13.9 pixels = 1 lm, applying the same criteria and cut-offs for tract assessment described in the original text. The re-analysis does not lead to any change in the conclusions from the experiments (i.e. rif1Δ delete and rif1-Δ C594 truncation mutants show nascent DNA degradation as originally described). As a consequence of this re-assessment, we have updated the sentence:"At 0 h (the time of HU addition), all three strains showing IdUlabelled tract of median length around 18 kb, consistent with an early stage of S phase when only some origins have initiated and bidirectional forks have travelled, on average, 9 kb each ( Fig 5C)." to read: "At 0 h (the time of HU addition), all three strains showing IdUlabelled tract of median length around 11.6 kb, consistent with an early stage of S phase when only some origins have initiated and bidirectional forks have travelled, on average, 5.8 kb each (Fig 5C)." and the sentence: "In rif1D cells, the nascent DNA tracts were in contrast noticeably eroded during the HU incubation period, with the median length decreasing from 21 to 13 kb in the first hour of the HU block." B IdU IdU C RIF1 rif1 rif1-C594 IdU tract length (kb) 0 20 40 60 0 1 1.5 0 1 1.5 0 1 1.5 hr in HU Figure 5B and C. Corrected figure. B IdU IdU C RIF1 rif1 rif1-C594 IdU tract length Figure 5B and C. Original figure.

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Mouse Rif1 is a regulatory subunit of protein phosphatase 1 (PP1)

Cited by 50 publications

References 55 publications

Rif1 functions in a tissue-specific manner to control replication timing through its PP1-binding motif

Rif1 functions in a tissue-specific manner to control replication timing through its PP1-binding motif

Nuclear organisation and replication timing are coupled through RIF1-PP1 interaction

Budding yeast Rif1 binds to replication origins and protects DNA at blocked replication forks

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