\u3cem\u3eVitis\u3c/em\u3e Seeds (Vitaceae) from the Late Neogene Gray Fossil Site, Northeastern Tennessee, USA.

This study focuses on the morphometric and systematic studies of fossil vitaceous seeds recently recovered from the Gray Fossil Site (7-4.5 Ma, latest Miocene-earliest Pliocene) northeastern Tennessee. Morphologically, all fossil seeds correspond to the extant subgenus Vitis (genus Vitis) of the Vitaceae based on the smooth dorsal surface with a centrally positioned chalaza connected with a conspicuous chalaza-apex groove and short linear ventral infolds that are slightly diverged apically. A multivariate analysis based on 11 measured characters from 76 complete seeds identified three types of seeds, each representing a distinct morphotaxon. Based on comparison with modern and fossil vitaceous specimens, three new species were recognized: Vitis grayana sp. nov., Vitis lanatoides sp. nov., and Vitis latisulcata sp.nov. The close resemblance between the first two fossil grapes (Vitis grayana and Vitis lanatoides) with extant eastern Asian Vitis provides further evidence that the eastern Asian floristic elements existing in the southeastern North American flora continued to as late as late Neogene

Role of bromodomain containing proteins in the DNA damage response

Chromatin-based DNA damage response (DDR) mechanisms are fundamental for preventing genome and epigenome instability, which are hallmarks of cancer. How chromatin promotes genome-epigenome integrity in response to DNA damage is a critical question. Chromatin acetylation is a key signaling event involved in detecting, signaling and repairing DNA damage. The bromodomain (BRD) containing protein is the primary reader of acetylation. Thus, BRD proteins represent attractive candidates for reading damaged chromatin to mediate genome-epigenome integrity. In the first part of this project, I performed a screen to analyze the dynamics of BRD protein at DNA damage sites. I identified one-third of BRD proteins relocalized upon DNA damage, a phenomenon common to DNA damage factors. In the second part of my thesis work, I functionally studied the BRD protein ZMYND8 in a novel transcription-dependent DNA damage recognition pathway. Upon DNA damage specifically within actively transcribing chromatin, ZMYND8 is recruited through its BRD to TIP60 mediated H4 acetylations. ZMYND8 associates with the NuRD complex and promotes its accumulation at damage sites to facilitate transcriptional repression and promote repair by homologous recombination (HR). To investigate mechanisms regulating this novel ZMYND8-NuRD pathway, I performed another screen to check the recruitment of ZMYND8 interacting factors as well as their effects on ZMYND8 recruitment. I identified the H3K4me3 specific histone demethylase KDM5A is a key upstream regulator of this transcription-dependent DNA damage recognition pathway. Upon DNA damage, KDM5A mediates the removal of H3K4me3 around active chromatin near damage sites, which is an essential step to facilitate recruitment of ZMYND8 and NuRD complex to DNA damage. Similar to ZMYND8 and NuRD, depletion of KDM5A also impairs damage induced transcriptional silencing and DNA double-strand break (DSB) repair by homologous recombination (HR). The DDR is not only a dynamic process focusing that regulates protein factor interaction at DNA damage sites, but also promotes transcriptional changes of some genes upon DNA damage. In another part of this project, I screened the functional role of BRD proteins in regulating transcription in response to different types of damage. I identified two novel p53 target genes SP110 and SP140. In response to treatment with the DNA damaging chemotherapeutic agent, Doxorubicin, in U2OS cells, SP110 and SP140 are upregulated in a p53 dependent manner. In summary, this study provides a comprehensive view for BRD reader proteins in promoting the DDR within acetylated chromatin to preserve genome-epigenome stability.Cellular and Molecular Biolog

Vitis Seeds (Vitaceae) From the Late Neogene Gray Fossil Site, Northeastern Tennessee, U.S.A.

This study focuses on morphometric and systematic analyses of the fossil Vitis seeds, recovered from the Gray Fossil Site (7-4.5. Ma, latest Miocene-earliest Pliocene), northeastern Tennessee, U.S.A. A multivariate analysis based on eleven measured characters from 76 complete fossil seeds recognizes three morphotaxa. Further comparisons with both selected modern and fossil vitaceous specimens confirm that these morphotaxa represent three new species, viz. Vitis grayensis sp. nov., Vitis lanatoides sp. nov., and Vitis latisulcata sp. nov. Furthermore, the close resemblance of the first two fossil grapes (V. grayensis and V. lanatoides) with two East Asian Vitis species provides further support concerning a strong eastern Asian aspect of the Gray fossil biota in the late Neogene southeastern North America, as previously evidenced by both animals (e.g. Pristinailurus bristoli [red panda]) and other plants (e.g. Sinomenium and Sargentodoxa)

FKBP25 participates in DNA double-strand break repair

FK506-binding proteins (FKBPs) alter the conformation of proteins via cis-trans isomerization of prolyl peptide bonds. While this activity can be demonstrated in vitro, the intractability of detecting prolyl isomerization events in cells has limited our understanding of the biological processes regulated by FKBPs. Here we report that FKBP25 is an active participant in the repair of DNA double-strand breaks (DSBs). FKBP25 influences DSB repair pathway choice by promoting homologous recombination (HR) and suppressing single-strand annealing (SSA). Consistent with this observation, cells depleted of FKBP25 form fewer Rad51 repair foci in response to etoposide and ionizing radiation, and they are reliant on the SSA repair factor, Rad52 for viability. We find that FKBP25â s catalytic activity is required for promoting DNA repair, which is the first description of a biological function for this enzyme activity. Consistent with the importance of the FKBP catalytic site in HR, rapamycin treatment also impairs homologous recombination, and this effect is at least in part independent of mTor. Taken together these results identify FKBP25 as a component of the DNA DSB repair pathway.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Acetylation Reader Proteins: Linking Acetylation Signaling to Genome Maintenance and Cancer - Fig 2

<p><b>Acety-lysine readers within (A) chromatin remodeling complexes and (B) BRD protein pathways involving DNA damage within transcriptionally active chromatin. (A and B).</b> Abbreviations: BRD, bromodomain; DSB, DNA double-strand break; ac, acetylation; me, methylation. Common and alternative names include: BRG1 (SMARCA4), BRM (SMARCA2), BAF180 (PBRM1), ACF1 (BAZ1A), WSTF (BAZ1B), KAP1 (TRIM28).</p

Acetylation signaling.

<p><b>(A)</b> HATs add an acetyl (Ac) moiety on the ε-amino group of a lysine residue, and HDACs reverse this reaction. <b>(B)</b> Acetylated lysines on histones are recognized and bound by proteins containing BRD domains and other acetyl-lysine binding domains. Abbreviations: ac, acetylation; HAT, histone acetyltransferase; HDAC, histone deacetylase; BRD, bromodomain; YEATS, Yaf9, ENL, AF9, Taf14, and Sas5; PHD, plant homeodomain; PH, pleckstrin-homology.</p

Model for the contribution of acetylation signaling in the DDR, cancer, and anticancer therapies that target epigenetic acetylation pathways.

<p>Abbreviations: ac, acetylation; BRD, bromodomain; HAT, histone acetyltransferase; HDAC, histone deacetylase.</p

A preoperative magnetic resonance imaging-based model to predict biochemical failure after radical prostatectomy

Abstract To investigate if a magnetic resonance imaging (MRI)-based model reduced postoperative biochemical failure (BF) incidence in patients with prostate cancer (PCa). From June 2018 to January 2020, we retrospectively analyzed 967 patients who underwent prostate bi-parametric MRI and radical prostatectomy (RP). After inclusion criteria were applied, 446 patients were randomized into research (n = 335) and validation cohorts (n = 111) at a 3:1 ratio. In addition to clinical variables, MRI models also included MRI parameters. The area under the curve (AUC) of receiver operating characteristic and decision curves were analyzed. The risk of postoperative BF, defined as persistently high or re-elevated prostate serum antigen (PSA) levels in patients with PCa with no clinical recurrence. In the research (age 69 [63–74] years) and validation cohorts (age 69 [64–74] years), the postoperative BF incidence was 22.39% and 27.02%, respectively. In the research cohort, the AUC of baseline and MRI models was 0.780 and 0.857, respectively, with a significant difference (P < 0.05). Validation cohort results were consistent (0.753 vs. 0.865, P < 0.05). At a 20% risk threshold, the false positive rate in the MRI model was lower when compared with the baseline model (31% [95% confidence interval (CI): 9–39%] vs. 44% [95% CI: 15–64%]), with the true positive rate only decreasing by a little (83% [95% CI: 63–94%] vs. 87% [95% CI: 75–100%]). 32 of 100 RPs can been performed, with no raise in quantity of patients with missed BF. We developed and verified a MRI-based model to predict BF incidence in patients after RP using preoperative clinical and MRI-related variables. This model could be used in clinical settings

Nucleosome Acidic Patch Promotes RNF168- and RING1B/BMI1-Dependent H2AX and H2A Ubiquitination and DNA Damage Signaling

Justin W. Leung, Poonam Agarwal, Fade Gong, Aaron D. Robison, Ilya J. Finkelstein, Kyle M. Miller, Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of AmericaJustin W. Leung, Poonam Agarwal, Fade Gong, Aaron D. Robison, Ilya J. Finkelstein, Kyle M. Miller, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas, United States of AmericaMarella D. Canny, Daniel Durocher, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, CanadaHistone ubiquitinations are critical for the activation of the DNA damage response (DDR). In particular, RNF168 and RING1B/BMI1 function in the DDR by ubiquitinating H2A/H2AX on Lys-13/15 and Lys-118/119, respectively. However, it remains to be defined how the ubiquitin pathway engages chromatin to provide regulation of ubiquitin targeting of specific histone residues. Here we identify the nucleosome acid patch as a critical chromatin mediator of H2A/H2AX ubiquitination (ub). The acidic patch is required for RNF168- and RING1B/BMI1-dependent H2A/H2AXub in vivo. The acidic patch functions within the nucleosome as nucleosomes containing a mutated acidic patch exhibit defective H2A/H2AXub by RNF168 and RING1B/BMI1 in vitro. Furthermore, direct perturbation of the nucleosome acidic patch in vivo by the expression of an engineered acidic patch interacting viral peptide, LANA, results in defective H2AXub and RNF168-dependent DNA damage responses including 53BP1 and BRCA1 recruitment to DNA damage. The acidic patch therefore is a critical nucleosome feature that may serve as a scaffold to integrate multiple ubiquitin signals on chromatin to compose selective ubiquitinations on histones for DNA damage signaling.The IJF laboratory was supported by the Welch Foundation (F-1808) and the Cancer Prevention Research Institute of Texas (CPRIT). DD is the Thomas Kierans Chair in Mechanisms of Cancer Development and a Canada Research Chair (Tier 1) in the Molecular Mechanisms of Genome Integrity. The DD laboratory was supported by CIHR grant MOP89754. The research in the KMM laboratory was supported in part by start-up funds from the University of Texas at Austin and from CPRIT (R116). KMM is a CPRIT scholar. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Molecular BiosciencesInstitute for Cellular and Molecular BiologyEmail: [email protected]