The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G 2 /M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1-3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle.

CDK4/6 inhibitors are being used to treat a variety of human malignancies. In well-differentiated and dedifferentiated liposarcoma their clinical promise is associated with their ability to downregulate the MDM2 protein. The downregulation of MDM2 following treatment with CDK4/6 inhibitors also induces many cultured tumor cell lines derived from different types of malignancies to progress from quiescence into senescence. Here we used cultured human cell lines and defined a role for PDLIM7 and CDH18, regulating MDM2 protein in CDK4/6 inhibitor-treated cells. Materials from our previous phase II trials with palbociclib were then used to demonstrate that expression of CDH18 protein was associated with response, measured as both progression-free survival and overall survival. This supports the hypothesis that the biologic transition from quiescence to senescence has clinical relevance for this class of drugs.

Ocular gene therapy with recombinant adeno-associated virus (AAV) has shown vector-mediated gene augmentation to be safe and efficacious in the retina in one set of diseases (retinitis pigmentosa and Leber congenital amaurosis (LCA) caused by RPE65 deficiency), with excellent safety profiles to date and potential for efficacy in several additional diseases. However, size constraints imposed by the packaging capacity of the AAV genome restrict application to diseases with coding sequence lengths that are less than 5,000 nt. The most prevalent retinal diseases with monogenic inheritance are caused by mutations in genes that exceed this capacity. Here, we designed a spliceosome mediated pre-mRNA trans-splicing strategy to rescue expression of CEP290, which is associated with Leber congenital amaurosis type 10 (LCA10) and several syndromic diseases including Joubert syndrome. We used this reagent to demonstrate editing of CEP290 in cell lines in vitro and in vivo in a mini-gene mouse model. This study is the first to show broad editing of CEP290 transcripts and in vivo proof of concept for editing of CEP290 transcripts in photoreceptors and paves the way for future studies evaluating therapeutic effects.

Griin' (Reg. No. CV-25, PI 672148), is a canola-quality, winter oilseed rape (Brassica napus L.) and is a dual-purpose forage and grain canola cultivar developed for Kansas, with potential to be grown across the southern Great Plains. It was tested as the experimental cultivar KS4022 and was released by K-State Research and Extension. The ability of Griin to withstand the efects of simulated grazing and its excellent forage quality compared with 'Wichita' make it a good candidate for dualpurpose use. In simulated grazing studies, Griin had winter survival superior to Wichita across all treatments; Griin averaged 80.4% survival across grazing treatments, whereas Wichita averaged 69.4%. At the optimum timing for forage harvest, Griin's inal grain yield was reduced by 36.6%, while Wichita's inal grain yield was reduced by 61.1% compared with the no-forage harvest treatment. Griin yields a highprotein, highly digestible, nutritious forage for livestock producers. Griin also possesses beneicial morphological features that could be used in breeding of new cultivars. A prostrate growth habit and the ability to avoid fall stem elongation are important characteristics to consider when selecting a canola cultivar with optimum winter survival.

‘Riley’ (Reg. No. CV‐24, PI 663949), a canola‐quality winter oilseed rape (Brassica napus L.), was developed and released by the Kansas Agricultural Experiment Station. Riley is a selection from the cross with pedigree KS3580/‘Jetton.’ Riley was tested in regional yield trials as the experimental variety KS4158 and was an entry in the National Winter Canola Variety Trial from 2008 through 2010. Riley was released because of its disease tolerance, improved oil content, and superior yield compared with ‘Wichita’ and other check varieties. The fatty acid profile and glucosinolate content of the meal of Riley are excellent quality. Riley had significantly greater yield than all check cultivars (P < 0.05), yielding 113% of Wichita and 116% of ‘DKW46‐15’. Through 27 site‐years on the southern Great Plains and High Plains, Riley averaged 400 g kg−1 total oil compared with Wichita's average of 388 g kg−1 (P < 0.05). The performance record of Riley suggests an increase in yield and consistency among commercial cultivars. As winter canola is planted on more hectares, demand is growing for improved genotypes.

Circadian clocks regulate multiple physiological processes in the eye, but their requirement for retinal health remains unclear. We previously showed that Drosophila homologs of spliceosome proteins implicated in human retinitis pigmentosa (RP), the most common genetically inherited cause of blindness, have a role in the brain circadian clock. In this study, we report circadian phenotypes in murine models of RP. We found that mice carrying a homozygous H2309P mutation in Pre-mRNA splicing factor 8 ( Prpf8) display a lengthened period of the circadian wheel-running activity rhythm. We show also that the daily cycling of circadian gene expression is dampened in the retina of Prpf8-H2309P mice. Surprisingly, molecular rhythms are intact in the eye cup, which includes the retinal pigment epithelium (RPE), even though the RPE is thought to be the primary tissue affected in this form of RP. Downregulation of Prp31, another RNA splicing factor implicated in RP, leads to period lengthening in a human cell culture model. The period of circadian bioluminescence in primary fibroblasts of human RP patients is not significantly altered. Together, these studies link a prominent retinal disorder to circadian deficits, which could contribute to disease pathology.

No abstract

Surefire' (Reg. no. CV-27, PI 689513) is a winter canola (Brassica napus L.) cultivar that possesses tolerance to sulfonylurea herbicide carryover in the soil. Surefire will replace 'Sumner', which was the first winter canola cultivar released with this tolerance for the southern Great Plains. Sulfonylurea herbicides, or acetolactate synthase (ALS) inhibitor herbicides, have significant plant-back restrictions for susceptible crops, and they often limit rotating to canola in wheat (Triticum aestivum L.)-based cropping systems. Planting tolerant cultivars allows canola producers to avoid the plant-back restrictions. Surefire was released by K-State Research and Extension and was tested under the experimental name KSUR1211. Surefire drew attention in the 2012-2013 growing season as an entry in the sulfonylurea residual tolerance yield trial. It was the top-ranked cultivar at Hutchinson and Manhattan, KS, averaging 3452 and 4232 kg ha −1 , respectively. Across Great Plains sites of the 2015-2016 and 2016-2017 National Winter Canola Variety Trial, Surefire averaged 522 kg ha −1 more than Sumner. Surefire is about 4.2 d later to 50% bloom than Sumner. Surefire does not differ from Sumner in its tolerance to sulfonylurea herbicide carryover. The later maturity of Surefire gives it a distinct yield advantage over Sumner as fuller-season cultivars typically yield more than early-maturity cultivars.