Abstract：
:Cells exposed to hypoxia experience replication stress but do not accumulate DNA damage, suggesting sustained DNA replication. Ribonucleotide reductase (RNR) is the only enzyme capable of de novo synthesis of deoxyribonucleotide triphosphates (dNTPs). However, oxygen is an essential cofactor for mammalian RNR (RRM1/RRM2 and RRM1/RRM2B), leading us to question the source of dNTPs in hypoxia. Here, we show that the RRM1/RRM2B enzyme is capable of retaining activity in hypoxia and therefore is favored over RRM1/RRM2 in order to preserve ongoing replication and avoid the accumulation of DNA damage. We found two distinct mechanisms by which RRM2B maintains hypoxic activity and identified responsible residues in RRM2B. The importance of RRM2B in the response to tumor hypoxia is further illustrated by correlation of its expression with a hypoxic signature in patient samples and its roles in tumor growth and radioresistance. Our data provide mechanistic insight into RNR biology, highlighting RRM2B as a hypoxic-specific, anti-cancer therapeutic target.
journal_name
Mol Celljournal_title
Molecular cellauthors
Foskolou IP,Jorgensen C,Leszczynska KB,Olcina MM,Tarhonskaya H,Haisma B,D'Angiolella V,Myers WK,Domene C,Flashman E,Hammond EMdoi
10.1016/j.molcel.2017.03.005subject
Has Abstractpub_date
2017-04-20 00:00:00pages
206-220.e9issue
2eissn
1097-2765issn
1097-4164pii
S1097-2765(17)30172-7journal_volume
66pub_type
杂志文章相关文献
MOLECULAR CELL文献大全abstract：:Cryo-EM structures of Dot1L in complex with a ubiquitinated nucleosome provide the long-sought-after molecular mechanism of Dot1L-mediated methylation of lysine 79 in histone H3 and explain crosstalk with histone H2B ubiquitination. ...
journal_title：Molecular cell
pub_type： 评论,杂志文章
doi：10.1016/j.molcel.2019.05.013
更新日期：2019-06-06 00:00:00
abstract：:Checkpoint proteins respond to DNA damage by halting the cell cycle until the damage is repaired. In this issue of Molecular Cell, Furuya et al. (2010) provide evidence that checkpoint proteins need to be removed from sites of damage in order to properly repair it. ...
journal_title：Molecular cell
pub_type： 评论,杂志文章
doi：10.1016/j.molcel.2010.11.015
更新日期：2010-11-24 00:00:00
abstract：:Superfamily ATPases in type IV pili, type 2 secretion, and archaella (formerly archaeal flagella) employ similar sequences for distinct biological processes. Here, we structurally and functionally characterize prototypical superfamily ATPase FlaI in Sulfolobus acidocaldarius, showing FlaI activities in archaeal swimmi...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2013.01.014
更新日期：2013-03-28 00:00:00
abstract：:In eukaryotes, three-dimensional genome organization is critical for transcriptional regulation of gene expression. Long noncoding RNAs (lncRNAs) can modulate chromatin conformation of spatially related genomic locations within the nucleus. Here, we show that the lncRNA APOLO (AUXIN-REGULATED PROMOTER LOOP) recognizes...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2019.12.015
更新日期：2020-03-05 00:00:00
abstract：:MicroRNAs (miRNAs) inhibit mRNA expression in general by base pairing to the 3'UTR of target mRNAs and consequently inhibiting translation and/or initiating poly(A) tail deadenylation and mRNA destabilization. Here we examine the mechanism and kinetics of miRNA-mediated deadenylation in mouse Krebs-2 ascites extract. ...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2009.08.004
更新日期：2009-09-24 00:00:00
abstract：:The proteolytic activation of the membrane-associated transcription factor pro-sigma(K) is controlled by a signal transduction pathway during sporulation in the bacterium Bacillus subtilis. The pro-sigma(K) processing enzyme SpoIVFB, a membrane-embedded metalloprotease, is held inactive by two other integral-membrane ...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2006.05.019
更新日期：2006-07-07 00:00:00
abstract：:Cellular DNA damage causes stabilization and activation of the tumor suppressor and transcription factor p53, in part by promoting multiple covalent modifications of the p53 protein, including acetylation. We investigated the importance of acetylation in p53 function and the mechanism by which acetylation influences p...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/s1097-2765(01)00414-2
更新日期：2001-12-01 00:00:00
abstract：:Atg7 is a noncanonical, homodimeric E1 enzyme that interacts with the noncanonical E2 enzyme, Atg3, to mediate conjugation of the ubiquitin-like protein (UBL) Atg8 during autophagy. Here we report that the unique N-terminal domain of Atg7 (Atg7(NTD)) recruits a unique "flexible region" from Atg3 (Atg3(FR)). The struct...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2011.08.034
更新日期：2011-11-04 00:00:00
abstract：:tRNAs reading four-codon families often have a modified uridine, cmo(5)U(34), at the wobble position of the anticodon. Here, we examine the effects on the decoding mechanism of a cmo(5)U modification in tRNA(1B)(Ala), anticodon C(36)G(35)cmo(5)U(34). tRNA(1B)(Ala) reads its cognate codons in a manner that is very simi...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2006.11.014
更新日期：2007-01-12 00:00:00
abstract：:To date, cross-species comparisons of genetic interactomes have been restricted to small or functionally related gene sets, limiting our ability to infer evolutionary trends. To facilitate a more comprehensive analysis, we constructed a genome-scale epistasis map (E-MAP) for the fission yeast Schizosaccharomyces pombe...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2012.05.028
更新日期：2012-06-08 00:00:00
abstract：:X chromosome inactivation (XCI) depends on a noncoding sense-antisense transcript pair, Xist and Tsix. At the onset of XCI, Xist RNA accumulates on one of two Xs, coating and silencing the chromosome in cis. The molecular basis for monoallelic Xist upregulation is not known, though evidence predominantly supports a po...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2006.01.028
更新日期：2006-03-03 00:00:00
abstract：:Nonsense-mediated decay (NMD) degrades mRNAs containing a premature termination codon (PTC). PTCs are a frequent cause of human genetic diseases, and the NMD pathway is known to modulate disease severity. Since partial NMD attenuation can potentially enhance nonsense suppression therapies, better definition of human-s...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2016.11.032
更新日期：2017-01-05 00:00:00
abstract：:Wu et al. (2019) establish that the active zone proteins RIM and RIM-BP undergo liquid-liquid phase separation to tether Ca2+ channels. This important finding sets a new framework to study assembly and function of the presynaptic nerve terminal. ...
journal_title：Molecular cell
pub_type： 评论,杂志文章
doi：10.1016/j.molcel.2019.02.020
更新日期：2019-03-07 00:00:00
abstract：:By using single-molecule fluorescence resonance energy transfer (smFRET), we observe the real-time dynamic coupling between the ribosome, labeled at the L1 stalk, and transfer RNA (tRNA). We find that an interaction between the ribosomal L1 stalk and the newly deacylated tRNA is established spontaneously upon peptide ...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2008.03.012
更新日期：2008-05-09 00:00:00
abstract：:The genomes of mammalian neurons contain uniquely high levels of non-CG DNA methylation that can be bound by the Rett syndrome protein, MeCP2, to regulate gene expression. How patterns of non-CG methylation are established in neurons and the mechanism by which this methylation works with MeCP2 to control gene expressi...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2019.10.033
更新日期：2020-01-16 00:00:00
abstract：:Repetitive DNA elements are essential for genome function; in this issue of Molecular Cell, Ishak et al. (2016) describe a novel mechanism of epigenetic repression at these elements that requires pRB-dependent recruitment of EZH2. ...
journal_title：Molecular cell
pub_type： 评论,杂志文章
doi：10.1016/j.molcel.2016.11.035
更新日期：2016-12-15 00:00:00
abstract：:Herpes simplex virus (HSV) infection requires binding of the viral envelope glycoprotein D (gD) to cell surface receptors. We report the X-ray structures of a soluble, truncated ectodomain of gD both alone and in complex with the ectodomain of its cellular receptor HveA. Two bound anions suggest possible binding sites...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/s1097-2765(01)00298-2
更新日期：2001-07-01 00:00:00
abstract：:In this issue, Roberts et al. (2014) describe how hexokinase and mTORC1 cooperate to sense disequilibrium between glucose uptake and utilization and direct the balance of anabolism and catabolism to ensure the appropriate use of cellular resources. ...
journal_title：Molecular cell
pub_type： 评论,杂志文章
doi：10.1016/j.molcel.2014.02.009
更新日期：2014-02-20 00:00:00
abstract：:Nucleosomes are surprisingly dynamic structures in vivo, showing transcription-independent exchange of histones H2A-H2B genome-wide and exchange of H3-H4 mainly within the promoters of transcribed genes. In addition, nucleosomes are disrupted in front of and reassembled behind the elongating RNA polymerase. Here we sh...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2009.07.001
更新日期：2009-08-14 00:00:00
abstract：:How repeating striped patterns arise across cellular fields is unclear. To address this we examined the repeating pattern of Stripe (Sr) expression across the parasegment (PS) in Drosophila. This pattern is generated in two steps. First, the ligands Hedgehog (Hh) and Wingless (Wg) subdivide the PS into smaller territo...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/s1097-2765(01)00163-0
更新日期：2001-01-01 00:00:00
abstract：:In a recent issue of Molecular Cell, use NMR to identify peptidyl-prolyl cis-trans isomerization as an autoinhibitory switch in the adaptor protein Crk, suggesting a new mechanism for controlling the rate of formation of signaling complexes. ...
journal_title：Molecular cell
pub_type： 评论,杂志文章
doi：10.1016/j.molcel.2007.02.005
更新日期：2007-02-23 00:00:00
abstract：:The Bloom syndrome helicase BLM and topoisomerase-IIβ-binding protein 1 (TopBP1) are key regulators of genome stability. It was recently proposed that BLM phosphorylation on Ser338 mediates its interaction with TopBP1, to protect BLM from ubiquitylation and degradation (Wang et al., 2013). Here, we show that the BLM-T...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2015.02.012
更新日期：2015-03-19 00:00:00
abstract：:The protein 53BP1 plays a central regulatory role in DNA double-strand break repair. 53BP1 relocates to chromatin by recognizing RNF168-mediated mono-ubiquitylation of histone H2A Lys15 in the nucleosome core particle dimethylated at histone H4 Lys20 (NCP-ubme). 53BP1 relocation is terminated by ubiquitin ligases RNF1...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2017.04.009
更新日期：2017-05-18 00:00:00
abstract：:Phase-separated states of proteins underlie ribonucleoprotein (RNP) granules and nuclear RNA-binding protein assemblies that may nucleate protein inclusions associated with neurodegenerative diseases. We report that the N-terminal low-complexity domain of the RNA-binding protein Fused in Sarcoma (FUS LC) is structural...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2015.09.006
更新日期：2015-10-15 00:00:00
abstract：:Members of the Wiskott-Aldrich syndrome protein (WASP) family control actin dynamics in eukaryotic cells by stimulating the actin nucleating activity of the Arp2/3 complex. The prevailing paradigm for WASP regulation invokes allosteric relief of autoinhibition by diverse upstream activators. Here we demonstrate an add...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2008.10.012
更新日期：2008-11-07 00:00:00
abstract：:The mechanisms by which telomeres are distinguished from DNA double-strand breaks are poorly understood. Here we have defined the minimal requirements for the protection of telomeric DNA ends from nonhomologous end-joining (NHEJ). Neither long, single-stranded overhangs nor t loop formation is essential to prevent NHE...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2007.03.023
更新日期：2007-05-11 00:00:00
abstract：:Crossover recombination is essential for accurate chromosome segregation during meiosis. The MutSγ complex, Msh4-Msh5, facilitates crossing over by binding and stabilizing nascent recombination intermediates. We show that these activities are governed by regulated proteolysis. MutSγ is initially inactive for crossing ...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2020.02.001
更新日期：2020-04-02 00:00:00
abstract：:Activation of NF-kappaB is achieved by ubiquitination and proteasome-mediated degradation of IkappaBalpha. We have detected modified IkappaBalpha, conjugated to the small ubiquitin-like protein SUMO-1, which is resistant to signal-induced degradation. In the presence of an E1 SUMO-1-activating enzyme, Ubch9 conjugated...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/s1097-2765(00)80133-1
更新日期：1998-08-01 00:00:00
abstract：:Metazoan histone mRNAs are unique: their pre-mRNAs contain no introns, and the mRNAs are not polyadenylated, ending instead in a conserved stem-loop structure. In Drosophila, canonical poly(A) signals are located downstream of the normal cleavage site of each histone gene and are utilized when histone 3' end formation...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2009.04.024
更新日期：2009-05-15 00:00:00
abstract：:The transcriptional activity of NF-kappa B is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase A (PKA). The transcriptional coactivator CPB/p300 associates with NF-kappa B p65 through two sites, an N-terminal domain that interacts with the C-terminal region of unphosphorylated p65, an...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/s1097-2765(00)80066-0
更新日期：1998-04-01 00:00:00
