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https://www.readbyqxmd.com/read/27812132/the-human-mixed-lineage-leukemia-5-mll5-a-sequentially-and-structurally-divergent-set-domain-containing-protein-with-no-intrinsic-catalytic-activity
#1
Sarah Mas-Y-Mas, Marta Barbon, Catherine Teyssier, Hélène Déméné, João E Carvalho, Louise E Bird, Andrey Lebedev, Juliana Fattori, Michael Schubert, Christian Dumas, William Bourguet, Albane le Maire
Mixed Lineage Leukemia 5 (MLL5) plays a key role in hematopoiesis, spermatogenesis and cell cycle progression. Chromatin binding is ensured by its plant homeodomain (PHD) through a direct interaction with the N-terminus of histone H3 (H3). In addition, MLL5 contains a Su(var)3-9, Enhancer of zeste, Trithorax (SET) domain, a protein module that usually displays histone lysine methyltransferase activity. We report here the crystal structure of the unliganded SET domain of human MLL5 at 2.1 Å resolution. Although it shows most of the canonical features of other SET domains, both the lack of key residues and the presence in the SET-I subdomain of an unusually large loop preclude the interaction of MLL5 SET with its cofactor and substrate...
2016: PloS One
https://www.readbyqxmd.com/read/27641306/dna-damage-induced-hspc-malfunction-depends-on-ros-accumulation-downstream-of-ifn-1-signaling-and-bid-mobilization
#2
Alpaslan Tasdogan, Suresh Kumar, Gabriele Allies, Julia Bausinger, Franziska Beckel, Helmut Hofemeister, Medhanie Mulaw, Vikas Madan, Karin Scharfetter-Kochanek, Michaela Feuring-Buske, Konstanze Doehner, Günter Speit, A Francis Stewart, Hans Joerg Fehling
Mouse mutants with an impaired DNA damage response frequently exhibit a set of remarkably similar defects in the HSPC compartment that are of largely unknown molecular basis. Using Mixed-Lineage-Leukemia-5 (Mll5)-deficient mice as prototypical examples, we have identified a mechanistic pathway linking DNA damage and HSPC malfunction. We show that Mll5 deficiency results in accumulation of DNA damage and reactive oxygen species (ROS) in HSPCs. Reduction of ROS efficiently reverses hematopoietic defects, establishing ROS as a major cause of impaired HSPC function...
December 1, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27002166/mll5-maintains-spindle-bipolarity-by-preventing-aberrant-cytosolic-aggregation-of-plk1
#3
Wei Zhao, Jie Liu, Xiaoming Zhang, Lih-Wen Deng
Faithful chromosome segregation with bipolar spindle formation is critical for the maintenance of genomic stability. Perturbation of this process often leads to severe mitotic failure, contributing to tumorigenesis. MLL5 has been demonstrated to play vital roles in cell cycle progression and the maintenance of genomic stability. Here, we identify a novel interaction between MLL5 and PLK1 in the cytosol that is crucial for sustaining spindle bipolarity during mitosis. Knockdown of MLL5 caused aberrant PLK1 aggregation that led to acentrosomal microtubule-organizing center (aMTOC) formation and subsequent spindle multipolarity...
March 28, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/26678539/mixed-lineage-leukemia-5-mll5-protein-stability-is-cooperatively-regulated-by-o-glcnac-transferase-ogt-and-ubiquitin-specific-protease-7-usp7
#4
Xiaodan Ding, Wei Jiang, Peipei Zhou, Lulu Liu, Xiaoling Wan, Xiujie Yuan, Xizi Wang, Miao Chen, Jun Chen, Jing Yang, Chao Kong, Bin Li, Chao Peng, Catherine C L Wong, Fajian Hou, Yan Zhang
Mixed lineage leukemia 5 (MLL5) protein is a trithorax family histone 3 lysine 4 (H3K4) methyltransferase that regulates diverse biological processes, including cell cycle progression, hematopoiesis and cancer. The mechanisms by which MLL5 protein stability is regulated have remained unclear to date. Here, we showed that MLL5 protein stability is cooperatively regulated by O-GlcNAc transferase (OGT) and ubiquitin-specific protease 7 (USP7). Depletion of OGT in cells led to a decrease in the MLL5 protein level through ubiquitin/proteasome-dependent proteolytic degradation, whereas ectopic expression of OGT protein suppressed MLL5 ubiquitylation...
2015: PloS One
https://www.readbyqxmd.com/read/26658778/mll5-promotes-self-renewing-glioblastoma-growth-via-h3-3-suppression
#5
(no author information available yet)
In adult GBM, MLL5 reduces H3.3 occupancy, globally reorganizes chromatin, and promotes self-renewal.
January 2016: Cancer Discovery
https://www.readbyqxmd.com/read/26626085/mll5-orchestrates-a-cancer-self-renewal-state-by-repressing-the-histone-variant-h3-3-and-globally-reorganizing-chromatin
#6
Marco Gallo, Fiona J Coutinho, Robert J Vanner, Tenzin Gayden, Stephen C Mack, Alex Murison, Marc Remke, Ren Li, Naoya Takayama, Kinjal Desai, Lilian Lee, Xiaoyang Lan, Nicole I Park, Dalia Barsyte-Lovejoy, David Smil, Dominik Sturm, Michelle M Kushida, Renee Head, Michael D Cusimano, Mark Bernstein, Ian D Clarke, John E Dick, Stefan M Pfister, Jeremy N Rich, Cheryl H Arrowsmith, Michael D Taylor, Nada Jabado, David P Bazett-Jones, Mathieu Lupien, Peter B Dirks
Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3...
December 14, 2015: Cancer Cell
https://www.readbyqxmd.com/read/25835095/functional-proteomics-of-the-epigenetic-regulators-asxl1-asxl2-and-asxl3-a-convergence-of-proteomics-and-epigenetics-for-translational-medicine
#7
REVIEW
Masaru Katoh
ASXL1, ASXL2 and ASXL3 are epigenetic scaffolds for BAP1, EZH2, NCOA1, nuclear receptors and WTIP. Here, functional proteomics of the ASXL family members are reviewed with emphasis on mutation spectra, the ASXM2 domain and the plant homeodomain (PHD) finger. Copy number gains of ASXL1 occur in chromosome 20q11.2 duplication syndrome and cervical cancer. Truncation mutations of ASXLs occur in autism, Bohring-Opitz and related syndromes, hematological malignancies and solid tumors, such as prostate cancer, breast cancer and high-grade glioma, which are gain- or loss-of-function mutations...
June 2015: Expert Review of Proteomics
https://www.readbyqxmd.com/read/25606435/association-of-the-histone-lysine-n-methyltransferase-mll5-gene-with-coronary-artery-disease-in-chinese-han-people
#8
Qinghua Yuan, Xiang Xie, Zhenyan Fu, Xiang Ma, Yining Yang, Ding Huang, Fen Liu, Chuanfang Dai, Yitong Ma
BACKGROUND: MLL5, a member of the histone-lysine N-methyltransferase family, has been implicated in the control of the cell cycle progression and survival. The aim of this study was to explore the relationship between the interaction of histone-lysine N-methyltransferase MLL5 gene polymorphism and CAD in a Chinese Han population. METHODS: Using a case-control study of Chinese CAD patients (n = 565) and healthy controls (n = 694), we investigated the MLL5 gene polymorphism by the use of polymerase chain reaction fragment length polymorphism (PCR-RFLP) analysis...
December 2014: Meta Gene
https://www.readbyqxmd.com/read/25547156/mouse-brwd1-is-critical-for-spermatid-postmeiotic-transcription-and-female-meiotic-chromosome-stability
#9
Shrivatsav Pattabiraman, Claudia Baumann, Daniela Guisado, John J Eppig, John C Schimenti, Rabindranath De La Fuente
Postmeiotic gene expression is essential for development and maturation of sperm and eggs. We report that the dual bromodomain-containing protein BRWD1, which is essential for both male and female fertility, promotes haploid spermatid-specific transcription but has distinct roles in oocyte meiotic progression. Brwd1 deficiency caused down-regulation of ∼300 mostly spermatid-specific transcripts in testis, including nearly complete elimination of those encoding the protamines and transition proteins, but was not associated with global epigenetic changes in chromatin, which suggests that BRWD1 acts selectively...
January 5, 2015: Journal of Cell Biology
https://www.readbyqxmd.com/read/25543507/-significance-of-chromosome-7-abnormalities-in-myeloid-malignancies
#10
REVIEW
Wen-Hui Shi, Xiao Li, Chun-Kang Chang
Chromosome 7 abnormalities are the most common cytogenetic alterations found in myeloid malignancies. Myeloid malignancies exhibiting monosomy 7/del (7q) have been confirmed to associate with high susceptibility to infections, poor response to chemotherapy, and short survival time, so speculating that chromosome 7 has important tumor suppressor genes. Commonly deleted segments (such as 7q22) of chromosome 7 have been identified by FISH and other technologies. Genes (EZH2, MLL5, DOCK4, SAMD9L/SAMD9) located in commonly deleted segments of 7q have been cloned and characterized along with the advance of molecular biology...
December 2014: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/25284784/de-novo-insertions-and-deletions-of-predominantly-paternal-origin-are-associated-with-autism-spectrum-disorder
#11
Shan Dong, Michael F Walker, Nicholas J Carriero, Michael DiCola, A Jeremy Willsey, Adam Y Ye, Zainulabedin Waqar, Luis E Gonzalez, John D Overton, Stephanie Frahm, John F Keaney, Nicole A Teran, Jeanselle Dea, Jeffrey D Mandell, Vanessa Hus Bal, Catherine A Sullivan, Nicholas M DiLullo, Rehab O Khalil, Jake Gockley, Zafer Yuksel, Sinem M Sertel, A Gulhan Ercan-Sencicek, Abha R Gupta, Shrikant M Mane, Michael Sheldon, Andrew I Brooks, Kathryn Roeder, Bernie Devlin, Matthew W State, Liping Wei, Stephan J Sanders
Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2...
October 9, 2014: Cell Reports
https://www.readbyqxmd.com/read/25176980/mll5-expression-as-a-biomarker-for-dna-hypermethylation-and-sensitivity-to-epigenetic-therapy
#12
EDITORIAL
Thomas A Milne
No abstract text is available yet for this article.
September 2014: Haematologica
https://www.readbyqxmd.com/read/25172963/targeted-silencing-of-mll5%C3%AE-inhibits-tumor-growth-and-promotes-gamma-irradiation-sensitization-in-hpv16-18-associated-cervical-cancers
#13
Dawn Sijin Nin, Chow Wenn Yew, Sun Kuie Tay, Lih-Wen Deng
We previously identified a novel MLL5 isoform, MLL5β, which was essential for E6 and E7 transcriptional activation in HPV16/18-associated cervical cancers. In this report, we investigated the potential of RNAi-mediated silencing of MLL5β through the use of MLL5β-siRNA as a novel therapeutic strategy for HPV16/18-positive cervical cancer. We observed concurrent downregulation of E6 and E7 after MLL5β silencing, leading to growth inhibition via the activation of apoptosis and senescence in the HeLa cell model...
November 2014: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/25135975/regulation-of-histone-h3k4-methylation-in-brain-development-and-disease
#14
REVIEW
Erica Shen, Hennady Shulha, Zhiping Weng, Schahram Akbarian
The growing list of mutations implicated in monogenic disorders of the developing brain includes at least seven genes (ARX, CUL4B, KDM5A, KDM5C, KMT2A, KMT2C, KMT2D) with loss-of-function mutations affecting proper regulation of histone H3 lysine 4 methylation, a chromatin mark which on a genome-wide scale is broadly associated with active gene expression, with its mono-, di- and trimethylated forms differentially enriched at promoter and enhancer and other regulatory sequences. In addition to these rare genetic syndromes, dysregulated H3K4 methylation could also play a role in the pathophysiology of some cases diagnosed with autism or schizophrenia, two conditions which on a genome-wide scale are associated with H3K4 methylation changes at hundreds of loci in a subject-specific manner...
September 26, 2014: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/24912499/regnet-mining-context-specific-human-transcription-networks-using-composite-genomic-information
#15
Sang-Mun Chi, Young-Kyo Seo, Young-Kyu Park, Sora Yoon, Chan Young Park, Yong Sung Kim, Seon-Young Kim, Dougu Nam
BACKGROUND: Genome-wide expression profiles reflect the transcriptional networks specific to the given cell context. However, most statistical models try to estimate the average connectivity of the networks from a collection of gene expression data, and are unable to characterize the context-specific transcriptional regulations. We propose an approach for mining context-specific transcription networks from a large collection of gene expression fold-change profiles and composite gene-set information...
2014: BMC Genomics
https://www.readbyqxmd.com/read/24895338/impact-of-mll5-expression-on-decitabine-efficacy-and-dna-methylation-in-acute-myeloid-leukemia
#16
Haiyang Yun, Frederik Damm, Damian Yap, Adrian Schwarzer, Anuhar Chaturvedi, Nidhi Jyotsana, Michael Lübbert, Lars Bullinger, Konstanze Döhner, Robert Geffers, Samuel Aparicio, R Keith Humphries, Arnold Ganser, Michael Heuser
Hypomethylating agents are widely used in patients with myelodysplastic syndromes and unfit patients with acute myeloid leukemia. However, it is not well understood why only some patients respond to hypomethylating agents. We found previously that the effect of decitabine on hematopoietic stem cell viability differed between Mll5 wild-type and null cells. We, therefore, investigated the role of MLL5 expression levels on outcome of acute myeloid leukemia patients who were treated with decitabine. MLL5 above the median expression level predicted longer overall survival independent of DNMT3A mutation status in bivariate analysis (median overall survival for high vs...
September 2014: Haematologica
https://www.readbyqxmd.com/read/24796963/prognostic-impact-of-kmt2e-transcript-levels-on-outcome-of-patients-with-acute-promyelocytic-leukaemia-treated-with-all-trans-retinoic-acid-and-anthracycline-based-chemotherapy-an-international-consortium-on-acute-promyelocytic-leukaemia-study
#17
Antonio R Lucena-Araujo, Haesook T Kim, Rafael H Jacomo, Raul A Melo, Rosane Bittencourt, Ricardo Pasquini, Katia Pagnano, Evandro M Fagundes, Maria de Lourdes Chauffaille, Carlos S Chiattone, Ana S Lima, Hau C Kwaan, Robert Gallagher, Charlotte M Niemeyer, Stanley L Schrier, Martin S Tallman, David Grimwade, Arnold Ganser, Nancy Berliner, Raul C Ribeiro, Francesco Lo-Coco, Bob Löwenberg, Miguel A Sanz, Eduardo M Rego
The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid-induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline-based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2-year overall survival (OS) (P = 0·005) and 2-year disease-free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2-year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04)...
August 2014: British Journal of Haematology
https://www.readbyqxmd.com/read/24586211/plasma-cholesterol-induced-lesion-networks-activated-before-regression-of-early-mature-and-advanced-atherosclerosis
#18
Johan L M Björkegren, Sara Hägg, Husain A Talukdar, Hassan Foroughi Asl, Rajeev K Jain, Cecilia Cedergren, Ming-Mei Shang, Aránzazu Rossignoli, Rabbe Takolander, Olle Melander, Anders Hamsten, Tom Michoel, Josefin Skogsberg
Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob (100/100) Mttp (flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage...
February 2014: PLoS Genetics
https://www.readbyqxmd.com/read/24130829/solution-nmr-structure-and-histone-binding-of-the-phd-domain-of-human-mll5
#19
Alexander Lemak, Adelinda Yee, Hong Wu, Damian Yap, Hong Zeng, Ludmila Dombrovski, Scott Houliston, Samuel Aparicio, Cheryl H Arrowsmith
Mixed Lineage Leukemia 5 (MLL5) is a histone methyltransferase that plays a key role in hematopoiesis, spermatogenesis and cell cycle progression. In addition to its catalytic domain, MLL5 contains a PHD finger domain, a protein module that is often involved in binding to the N-terminus of histone H3. Here we report the NMR solution structure of the MLL5 PHD domain showing a variant of the canonical PHD fold that combines conserved H3 binding features from several classes of other PHD domains (including an aromatic cage) along with a novel C-terminal α-helix, not previously seen...
2013: PloS One
https://www.readbyqxmd.com/read/23798402/molecular-basis-for-chromatin-binding-and-regulation-of-mll5
#20
Muzaffar Ali, Héctor Rincón-Arano, Wei Zhao, Scott B Rothbart, Qiong Tong, Susan M Parkhurst, Brian D Strahl, Lih-Wen Deng, Mark Groudine, Tatiana G Kutateladze
The human mixed-lineage leukemia 5 (MLL5) protein mediates hematopoietic cell homeostasis, cell cycle, and survival; however, the molecular basis underlying MLL5 activities remains unknown. Here, we show that MLL5 is recruited to gene-rich euchromatic regions via the interaction of its plant homeodomain finger with the histone mark H3K4me3. The 1.48-Å resolution crystal structure of MLL5 plant homeodomain in complex with the H3K4me3 peptide reveals a noncanonical binding mechanism, whereby K4me3 is recognized through a single aromatic residue and an aspartate...
July 9, 2013: Proceedings of the National Academy of Sciences of the United States of America
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