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Genes & Development

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https://www.readbyqxmd.com/read/28336516/a-novel-role-of-the-dna2-translocase-function-in-dna-break-resection
#1
Adam S Miller, James M Daley, Nhung Tuyet Pham, Hengyao Niu, Xiaoyu Xue, Grzegorz Ira, Patrick Sung
DNA double-strand break repair by homologous recombination entails nucleolytic resection of the 5' strand at break ends. Dna2, a flap endonuclease with 5'-3' helicase activity, is involved in the resection process. The Dna2 helicase activity has been implicated in Okazaki fragment processing during DNA replication but is thought to be dispensable for DNA end resection. Unexpectedly, we found a requirement for the helicase function of Dna2 in end resection in budding yeast cells lacking exonuclease 1. Biochemical analysis reveals that ATP hydrolysis-fueled translocation of Dna2 on ssDNA facilitates 5' flap cleavage near a single-strand-double strand junction while attenuating 3' flap incision...
March 23, 2017: Genes & Development
https://www.readbyqxmd.com/read/28336515/the-motor-activity-of-dna2-functions-as-an-ssdna-translocase-to-promote-dna-end-resection
#2
Maryna Levikova, Cosimo Pinto, Petr Cejka
DNA2 nuclease-helicase functions in DNA replication and recombination. This requires the nuclease of DNA2, while, in contrast, the role of the helicase activity has been unclear. We now show that the motor activity of both recombinant yeast and human DNA2 promotes efficient degradation of long stretches of ssDNA, particularly in the presence of the replication protein A. This degradation is further stimulated by a direct interaction with a cognate RecQ family helicase, which functions with DNA2 in DNA end resection to initiate homologous recombination...
March 23, 2017: Genes & Development
https://www.readbyqxmd.com/read/28289143/transcription-factor-wilms-tumor-1-regulates-developmental-rnas-through-3-utr-interaction
#3
Ruthrothaselvi Bharathavikru, Tatiana Dudnakova, Stuart Aitken, Joan Slight, Mara Artibani, Peter Hohenstein, David Tollervey, Nick Hastie
Wilms' tumor 1 (WT1) is essential for the development and homeostasis of multiple mesodermal tissues. Despite evidence for post-transcriptional roles, no endogenous WT1 target RNAs exist. Using RNA immunoprecipitation and UV cross-linking, we show that WT1 binds preferentially to 3' untranslated regions (UTRs) of developmental targets. These target mRNAs are down-regulated upon WT1 depletion in cell culture and developing kidney mesenchyme. Wt1 deletion leads to rapid turnover of specific mRNAs. WT1 regulates reporter gene expression through interaction with 3' UTR-binding sites...
March 13, 2017: Genes & Development
https://www.readbyqxmd.com/read/28279982/a-prosurvival-dna-damage-induced-cytoplasmic-interferon-response-is-mediated-by-end-resection-factors-and-is-limited-by-trex1
#4
Erkin Erdal, Syed Haider, Jan Rehwinkel, Adrian L Harris, Peter J McHugh
Radiotherapy and chemotherapy are effective treatment methods for many types of cancer, but resistance is common. Recent findings indicate that antiviral type I interferon (IFN) signaling is induced by these treatments. However, the underlying mechanisms still need to be elucidated. Expression of a set of IFN-stimulated genes comprises an IFN-related DNA damage resistance signature (IRDS), which correlates strongly with resistance to radiotherapy and chemotherapy across different tumors. Classically, during viral infection, the presence of foreign DNA in the cytoplasm of host cells can initiate type I IFN signaling...
March 9, 2017: Genes & Development
https://www.readbyqxmd.com/read/28275002/high-constitutive-activity-of-a-broad-panel-of-housekeeping-and-tissue-specific-cis-regulatory-elements-depends-on-a-subset-of-ets-proteins
#5
Alessia Curina, Alberto Termanini, Iros Barozzi, Elena Prosperini, Marta Simonatto, Sara Polletti, Alessio Silvola, Monica Soldi, Liv Austenaa, Tiziana Bonaldi, Serena Ghisletti, Gioacchino Natoli
Enhancers and promoters that control the transcriptional output of terminally differentiated cells include cell type-specific and broadly active housekeeping elements. Whether the high constitutive activity of these two groups of cis-regulatory elements relies on entirely distinct or instead also on shared regulators is unknown. By dissecting the cis-regulatory repertoire of macrophages, we found that the ELF subfamily of ETS proteins selectively bound within 60 base pairs (bp) from the transcription start sites of highly active housekeeping genes...
March 8, 2017: Genes & Development
https://www.readbyqxmd.com/read/28275001/pancreatic-%C3%AE-and-%C3%AE-cellular-clocks-have-distinct-molecular-properties-and-impact-on-islet-hormone-secretion-and-gene-expression
#6
Volodymyr Petrenko, Camille Saini, Laurianne Giovannoni, Cedric Gobet, Daniel Sage, Michael Unser, Mounia Heddad Masson, Guoqiang Gu, Domenico Bosco, Frédéric Gachon, Jacques Philippe, Charna Dibner
A critical role of circadian oscillators in orchestrating insulin secretion and islet gene transcription has been demonstrated recently. However, these studies focused on whole islets and did not explore the interplay between α-cell and β-cell clocks. We performed a parallel analysis of the molecular properties of α-cell and β-cell oscillators using a mouse model expressing three reporter genes: one labeling α cells, one specific for β cells, and a third monitoring circadian gene expression. Thus, phase entrainment properties, gene expression, and functional outputs of the α-cell and β-cell clockworks could be assessed in vivo and in vitro at the population and single-cell level...
March 8, 2017: Genes & Development
https://www.readbyqxmd.com/read/28242626/atr-inhibition-disrupts-rewired-homologous-recombination-and-fork-protection-pathways-in-parp-inhibitor-resistant-brca-deficient-cancer-cells
#7
Stephanie A Yazinski, Valentine Comaills, Rémi Buisson, Marie-Michelle Genois, Hai Dang Nguyen, Chu Kwen Ho, Tanya Todorova Kwan, Robert Morris, Sam Lauffer, André Nussenzweig, Sridhar Ramaswamy, Cyril H Benes, Daniel A Haber, Shyamala Maheswaran, Michael J Birrer, Lee Zou
Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance...
February 27, 2017: Genes & Development
https://www.readbyqxmd.com/read/28242625/zmym3-regulates-brca1-localization-at-damaged-chromatin-to-promote-dna-repair
#8
Justin W C Leung, Nodar Makharashvili, Poonam Agarwal, Li-Ya Chiu, Renaud Pourpre, Michael B Cammarata, Joe R Cannon, Alana Sherker, Daniel Durocher, Jennifer S Brodbelt, Tanya T Paull, Kyle M Miller
Chromatin connects DNA damage response factors to sites of damaged DNA to promote the signaling and repair of DNA lesions. The histone H2A variants H2AX, H2AZ, and macroH2A represent key chromatin constituents that facilitate DNA repair. Through proteomic screening of these variants, we identified ZMYM3 (zinc finger, myeloproliferative, and mental retardation-type 3) as a chromatin-interacting protein that promotes DNA repair by homologous recombination (HR). ZMYM3 is recruited to DNA double-strand breaks through bivalent interactions with both histone and DNA components of the nucleosome...
February 27, 2017: Genes & Development
https://www.readbyqxmd.com/read/28235849/crl2-lrr1-promotes-unloading-of-the-vertebrate-replisome-from-chromatin-during-replication-termination
#9
James M Dewar, Emily Low, Matthias Mann, Markus Räschle, Johannes C Walter
A key event during eukaryotic replication termination is the removal of the CMG helicase from chromatin. CMG unloading involves ubiquitylation of its Mcm7 subunit and the action of the p97 ATPase. Using a proteomic screen in Xenopus egg extracts, we identified factors that are enriched on chromatin when CMG unloading is blocked. This approach identified the E3 ubiquitin ligase CRL2(Lrr1), a specific p97 complex, other potential regulators of termination, and many replisome components. We show that Mcm7 ubiquitylation and CRL2(Lrr1) binding to chromatin are temporally linked and occur only during replication termination...
February 24, 2017: Genes & Development
https://www.readbyqxmd.com/read/28223312/natural-variation-and-dosage-of-the-hei10-meiotic-e3-ligase-control-arabidopsis-crossover-recombination
#10
Piotr A Ziolkowski, Charles J Underwood, Christophe Lambing, Marina Martinez-Garcia, Emma J Lawrence, Liliana Ziolkowska, Catherine Griffin, Kyuha Choi, F Chris H Franklin, Robert A Martienssen, Ian R Henderson
During meiosis, homologous chromosomes undergo crossover recombination, which creates genetic diversity and balances homolog segregation. Despite these critical functions, crossover frequency varies extensively within and between species. Although natural crossover recombination modifier loci have been detected in plants, causal genes have remained elusive. Using natural Arabidopsis thaliana accessions, we identified two major recombination quantitative trait loci (rQTLs) that explain 56.9% of crossover variation in Col×Ler F2 populations...
February 21, 2017: Genes & Development
https://www.readbyqxmd.com/read/28223311/single-tumor-initiating-cells-evade-immune-clearance-by-recruiting-type-ii-macrophages
#11
Xiaocan Guo, Yang Zhao, Huan Yan, Yingcheng Yang, Shuying Shen, Xiaoming Dai, Xinyan Ji, Fubo Ji, Xing-Guo Gong, Li Li, Xueli Bai, Xin-Hua Feng, Tingbo Liang, Junfang Ji, Lei Chen, Hongyang Wang, Bin Zhao
Tumor infiltrated type II (M2) macrophages promote tumorigenesis by suppressing immune clearance, promoting proliferation, and stimulating angiogenesis. Interestingly, macrophages were also found to enrich in small foci of altered hepatocytes containing liver tumor-initiating cells (TICs). However, whether and how TICs specifically recruit macrophages and the function of these macrophages in tumor initiation remain unknown due to technical difficulties. In this study, by generating genetically defined liver TICs, we demonstrate that TICs actively recruit M2 macrophages from as early as the single-cell stage...
February 21, 2017: Genes & Development
https://www.readbyqxmd.com/read/28314766/the-metabolic-programming-of-stem-cells
#12
REVIEW
Ng Shyh-Chang, Huck-Hui Ng
Advances in metabolomics have deepened our understanding of the roles that specific modes of metabolism play in programming stem cell fates. Here, we review recent metabolomic studies of stem cell metabolism that have revealed how metabolic pathways can convey changes in the extrinsic environment or their niche to program stem cell fates. The metabolic programming of stem cells represents a fine balance between the intrinsic needs of a cellular state and the constraints imposed by extrinsic conditions. A more complete understanding of these needs and constraints will afford us greater mastery over our control of stem cell fates...
February 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28314765/no-back-seat-for-a-progression-event-k-ras-as-a-therapeutic-target-in-crc
#13
REVIEW
Emily J Poulin, Kevin M Haigis
KRAS is the most frequently mutated oncogene in human cancer and plays a central, although poorly understood, role in colorectal cancer (CRC) progression. In this issue of Genes & Development, Boutin and colleagues (pp. 370-382) present a new mouse model of CRC in which the expression of oncogenic K-RAS is regulated by doxycycline. Using this model, they demonstrate that continued expression of oncogenic K-RAS is required for the survival of primary and metastatic colon cancers and that oncogenic K-RAS activates TGF-β signaling to promote tumor invasion and metastasis...
February 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28289142/transcriptional-interference-by-rna-polymerase-iii-affects-expression-of-the-polr3e-gene
#14
Meghdad Yeganeh, Viviane Praz, Pascal Cousin, Nouria Hernandez
Overlapping gene arrangements can potentially contribute to gene expression regulation. A mammalian interspersed repeat (MIR) nested in antisense orientation within the first intron of the Polr3e gene, encoding an RNA polymerase III (Pol III) subunit, is conserved in mammals and highly occupied by Pol III. Using a fluorescence assay, CRISPR/Cas9-mediated deletion of the MIR in mouse embryonic stem cells, and chromatin immunoprecipitation assays, we show that the MIR affects Polr3e expression through transcriptional interference...
February 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28289141/oncogenic-kras-drives-invasion-and-maintains-metastases-in-colorectal-cancer
#15
Adam T Boutin, Wen-Ting Liao, Melody Wang, Soyoon Sarah Hwang, Tatiana V Karpinets, Hannah Cheung, Gerald C Chu, Shan Jiang, Jian Hu, Kyle Chang, Eduardo Vilar, Xingzhi Song, Jianhua Zhang, Scott Kopetz, Andrew Futreal, Y Alan Wang, Lawrence N Kwong, Ronald A DePinho
Human colorectal cancer (CRC) is a major cause of cancer mortality and frequently harbors activating mutations in the KRAS gene. To understand the role of oncogenic KRAS in CRC, we engineered a mouse model of metastatic CRC that harbors an inducible oncogenic Kras allele (Kras(mut) ) and conditional null alleles of Apc and Trp53 (iKAP). The iKAP model recapitulates tumor progression from adenoma through metastases. Whole-exome sequencing revealed that the Kras(mut) allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated Kras(mut) signaling being a driver of progression to metastasis...
February 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28279983/a-microrna-family-exerts-maternal-control-on-sex-determination-in-c-elegans
#16
Katherine McJunkin, Victor Ambros
Gene expression in early animal embryogenesis is in large part controlled post-transcriptionally. Maternally contributed microRNAs may therefore play important roles in early development. We elucidated a major biological role of the nematode mir-35 family of maternally contributed essential microRNAs. We show that this microRNA family regulates the sex determination pathway at multiple levels, acting both upstream of and downstream from her-1 to prevent aberrantly activated male developmental programs in hermaphrodite embryos...
February 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28270517/mcm10-regulates-dna-replication-elongation-by-stimulating-the-cmg-replicative-helicase
#17
Marko Lõoke, Michael F Maloney, Stephen P Bell
Activation of the Mcm2-7 replicative DNA helicase is the committed step in eukaryotic DNA replication initiation. Although Mcm2-7 activation requires binding of the helicase-activating proteins Cdc45 and GINS (forming the CMG complex), an additional protein, Mcm10, drives initial origin DNA unwinding by an unknown mechanism. We show that Mcm10 binds a conserved motif located between the oligonucleotide/oligosaccharide fold (OB-fold) and A subdomain of Mcm2. Although buried in the interface between these domains in Mcm2-7 structures, mutations predicted to separate the domains and expose this motif restore growth to conditional-lethal MCM10 mutant cells...
February 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28270516/cbx3-maintains-lineage-specificity-during-neural-differentiation
#18
Chengyang Huang, Trent Su, Yong Xue, Chen Cheng, Fides D Lay, Robin A McKee, Meiyang Li, Ajay Vashisht, James Wohlschlegel, Bennett G Novitch, Kathrin Plath, Siavash K Kurdistani, Michael Carey
Chromobox homolog 3 (Cbx3/heterochromatin protein 1γ [HP1γ]) stimulates cell differentiation, but its mechanism is unknown. We found that Cbx3 binds to gene promoters upon differentiation of murine embryonic stem cells (ESCs) to neural progenitor cells (NPCs) and recruits the Mediator subunit Med26. RNAi knockdown of either Cbx3 or Med26 inhibits neural differentiation while up-regulating genes involved in mesodermal lineage decisions. Thus, Cbx3 and Med26 together ensure the fidelity of lineage specification by enhancing the expression of neural genes and down-regulating genes specific to alternative fates...
February 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28270515/all-mixed-up-defining-roles-for-%C3%AE-cell-subtypes-in-mature-islets
#19
REVIEW
Jennifer S E Liu, Matthias Hebrok
Following differentiation during fetal development, β cells further adapt to their postnatal role through functional maturation. While adult islets are thought to contain functionally mature β cells, recent analyses of transgenic rodent and human pancreata reveal a number of novel heterogeneity markers in mammalian β cells. The marked heterogeneity long after maturation raises the prospect that diverse populations harbor distinct roles aside from glucose-stimulated insulin secretion. In this review, we outline our current understanding of the β-cell maturation process, emphasize recent literature on novel heterogeneity markers, and offer perspectives on reconciling the findings from these two areas...
February 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28270514/conducting-the-finale-of-dna-replication
#20
REVIEW
David Akopian, Michael Rape
Anomalies in dismantling the machinery of DNA replication can compromise genome integrity and contribute to tumorigenesis and aging. In this issue of Genes & Development, Dewar and colleagues (pp. 275-290) identified an E3 ubiquitin ligase, CUL2(LRR2), that modifies a subunit of the replicative CMG (Cdc45, minichromosome maintenance [MCM] subunits 2-7, and the GINS complex) helicase and triggers disassembly of the replication machinery. Their study offers critical insight into the mechanism of DNA replication termination while at the same time raising important questions for future research...
February 1, 2017: Genes & Development
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