Abstract:
:MRE11 within the MRE11-RAD50-NBS1 (MRN) complex acts in DNA double-strand break repair (DSBR), detection, and signaling; yet, how its endo- and exonuclease activities regulate DSBR by nonhomologous end-joining (NHEJ) versus homologous recombination (HR) remains enigmatic. Here, we employed structure-based design with a focused chemical library to discover specific MRE11 endo- or exonuclease inhibitors. With these inhibitors, we examined repair pathway choice at DSBs generated in G2 following radiation exposure. While nuclease inhibition impairs radiation-induced replication protein A (RPA) chromatin binding, suggesting diminished resection, the inhibitors surprisingly direct different repair outcomes. Endonuclease inhibition promotes NHEJ in lieu of HR, while exonuclease inhibition confers a repair defect. Collectively, the results describe nuclease-specific MRE11 inhibitors, define distinct nuclease roles in DSB repair, and support a mechanism whereby MRE11 endonuclease initiates resection, thereby licensing HR followed by MRE11 exonuclease and EXO1/BLM bidirectional resection toward and away from the DNA end, which commits to HR.
journal_name
Mol Celljournal_title
Molecular cellauthors
Shibata A,Moiani D,Arvai AS,Perry J,Harding SM,Genois MM,Maity R,van Rossum-Fikkert S,Kertokalio A,Romoli F,Ismail A,Ismalaj E,Petricci E,Neale MJ,Bristow RG,Masson JY,Wyman C,Jeggo PA,Tainer JAdoi
10.1016/j.molcel.2013.11.003subject
Has Abstractpub_date
2014-01-09 00:00:00pages
7-18issue
1eissn
1097-2765issn
1097-4164pii
S1097-2765(13)00828-9journal_volume
53pub_type
杂志文章相关文献
MOLECULAR CELL文献大全abstract::During muscle regeneration, the mechanism integrating environmental cues at the chromatin of muscle progenitors is unknown. We show that inflammation-activated MKK6-p38 and insulin growth factor 1 (IGF1)-induced PI3K/AKT pathways converge on the chromatin of muscle genes to target distinct components of the muscle tra...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2007.08.021
更新日期:2007-10-26 00:00:00
abstract::Molecular motors are the long-haul carriers of eukaryotic cells, moving cargos bidirectionally along microtubule tracks. In the December 12th issue of Cell, report that HDAC6, a tubulin deacetylase, functions as an adaptor that links cargos of aggregated protein to the minus end-directed motor, cytoplasmic dynein. ...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/s1097-2765(03)00498-2
更新日期:2003-12-01 00:00:00
abstract::Ubiquitination typically occurs through the sequential action of three enzymes catalyzing ubiquitin activation (E1), conjugation (E2), and ligation (E3) and regulates diverse eukaryotic cellular processes. Although monoubiquitination commonly confers nondegradative activities, mechanisms underlying its temporal and sp...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2016.04.022
更新日期:2016-06-16 00:00:00
abstract::Cdh1 is a well-established activator of APC/C, a RING-type ubiquitin ligase. In this issue of Molecular Cell, Wan et al. (2011) report an APC/C-independent role of Cdh1 during development as an activator for Smurf1, a HECT-type ubiquitin ligase. ...
journal_title:Molecular cell
pub_type: 评论,杂志文章
doi:10.1016/j.molcel.2011.11.012
更新日期:2011-12-09 00:00:00
abstract::Cas9 is a prokaryotic RNA-guided DNA endonuclease that binds substrates tightly in vitro but turns over rapidly when used to manipulate genomes in eukaryotic cells. Little is known about the factors responsible for dislodging Cas9 or how they influence genome engineering. Unbiased detection through proximity labeling ...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2020.06.014
更新日期:2020-07-16 00:00:00
abstract::PTPA, an essential and specific activator of protein phosphatase 2A (PP2A), functions as a peptidyl prolyl isomerase (PPIase). We present here the crystal structures of human PTPA and of the two yeast orthologs (Ypa1 and Ypa2), revealing an all alpha-helical protein fold that is radically different from other PPIases....
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2006.07.008
更新日期:2006-08-04 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::RNA molecules play diverse functional roles in natural biological systems. There has been growing interest in designing synthetic RNA counterparts for programming biological function. The design of synthetic RNA molecules that exhibit diverse activities, including sensing, regulatory, information processing, and scaff...
journal_title:Molecular cell
pub_type: 杂志文章,评审
doi:10.1016/j.molcel.2011.08.023
更新日期:2011-09-16 00:00:00
abstract::The role of the protein kinase Akt in cell migration is incompletely understood. Here we show that sphingosine-1-phosphate (S1P)-induced endothelial cell migration requires the Akt-mediated phosphorylation of the G protein-coupled receptor (GPCR) EDG-1. Activated Akt binds to EDG-1 and phosphorylates the third intrace...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/s1097-2765(01)00324-0
更新日期:2001-09-01 00:00:00
abstract::One of the prominent biological phenomena controlled by Wnt signaling is the expansion of cells with predefined fates. In the November 27, 2002, issue of Cell, Rosenfeld and colleagues describe an example of Wnt-controlled proliferation during genesis of the cardiac outflow tract and the pituitary gland. As a downstre...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/s1097-2765(02)00801-8
更新日期:2002-12-01 00:00:00
abstract::Unscheduled RNA-DNA hybrids promote the formation DNA double-strand breaks (DSBs) through poorly characterized mechanism. In this issue, Sollier et al. (2014) show that R-loops are processed by XPF and XPG, two structure-specific endonucleases of the NER pathway, to generate DSBs. ...
journal_title:Molecular cell
pub_type: 评论,杂志文章
doi:10.1016/j.molcel.2014.12.011
更新日期:2014-12-18 00:00:00
abstract::In bacteria, RNA polymerase (RNAP) initiates transcription by synthesizing short transcripts that are either released or extended to allow RNAP to escape from the promoter. The mechanism of initial transcription is unclear due to the presence of transient intermediates and molecular heterogeneity. Here, we studied ini...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2016.08.011
更新日期:2016-09-15 00:00:00
abstract::Tethering of synaptic vesicles (SVs) to the active zone determines synaptic strength, although the molecular basis governing SV tethering is elusive. Here, we discover that small unilamellar vesicles (SUVs) and SVs from rat brains coat on the surface of condensed liquid droplets formed by active zone proteins RIM, RIM...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2020.10.029
更新日期:2021-01-07 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::A defining feature of centromeres is the presence of the histone H3 variant CENP-A(Cnp1). It is not known how CENP-A(Cnp1) is specifically delivered to, and assembled into, centromeric chromatin. Through a screen for factors involved in kinetochore integrity in fission yeast, we identified Sim3. Sim3 is homologous to ...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2007.10.010
更新日期:2007-12-28 00:00:00
abstract::In response to hyperosmotic environments, most eukaryotic cells activate a specialized mitogen-activated protein (MAP) kinase pathway. In S. cerevisiae, the key protein kinase, Hog1, coordinates the transcriptional induction of a variety of genes devoted to osmoadaptation and general stress protection. Depending on th...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/s1097-2765(01)00221-0
更新日期:2001-04-01 00:00:00
abstract::B cell CLL/lymphoma-2 (BCL-2) and its relatives comprise the BCL-2 family of proteins, which were originally characterized with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis. Current observations expand BCL-2 family function to include numerous cellular pathways. Here we wi...
journal_title:Molecular cell
pub_type: 杂志文章,评审
doi:10.1016/j.molcel.2010.01.025
更新日期:2010-02-12 00:00:00
abstract::The C-terminal fragment, Bb, of factor B combines with C3b to form the pivotal C3-convertase, C3bBb, of alternative complement pathway. Bb consists of a von Willebrand factor type A (vWFA) domain that is structurally similar to the I domains of integrins and a serine protease (SP) domain that is in inactive conformati...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/s1097-2765(04)00160-1
更新日期:2004-04-09 00:00:00
abstract::The ER-mitochondrial junction provides a local calcium signaling domain that is critical for both matching energy production with demand and the control of apoptosis. Here, we visualize ER-mitochondrial contact sites and monitor the localized [Ca(2+)] changes ([Ca(2+)](ER-mt)) using drug-inducible fluorescent interorg...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2010.06.029
更新日期:2010-07-09 00:00:00
abstract::Transcription and splicing are functionally coupled, resulting in highly efficient splicing of RNA polymerase II (RNAP II) transcripts. The mechanism involved in this coupling is not known. To identify potential coupling factors, we carried out a comprehensive proteomic analysis of immunopurified human RNAP II, identi...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2007.05.036
更新日期:2007-06-22 00:00:00
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/RR...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2017.03.005
更新日期:2017-04-20 00:00:00
abstract::N6-methyladenosine (m6A) and adenosine-to-inosine (A-to-I) editing are two of the most abundant RNA modifications, both at adenosines. Yet, the interaction of these two types of adenosine modifications is largely unknown. Here we show a global A-to-I difference between m6A-positive and m6A-negative RNA populations. Bo...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2017.12.006
更新日期:2018-01-04 00:00:00
abstract::Two cyclin-dependent kinases have been identified in yeast and mammalian RNA polymerase II transcription initiation complexes. We find that the two yeast kinases are indistinguishable in their ability to phosphorylate the RNA polymerase II CTD, and yet in living cells one kinase is a positive regulator and the other a...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/s1097-2765(00)80112-4
更新日期:1998-07-01 00:00:00
abstract::Steroid hormones have rapid nongenomic effects on cell-signaling pathways, but the receptor mechanisms responsible for this are not understood. We have identified a specific polyproline motif in the amino-terminal domain of conventional progesterone receptor (PR) that mediates direct progestin-dependent interaction of...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/s1097-2765(01)00304-5
更新日期:2001-08-01 00:00:00
abstract::Spt6 is an essential histone chaperone that mediates nucleosome reassembly during gene transcription. Spt6 also associates with RNA polymerase II (RNAPII) via a tandem Src2 homology domain. However, the significance of Spt6-RNAPII interaction is not well understood. Here, we show that Spt6 recruitment to genes and the...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2018.05.020
更新日期:2018-06-21 00:00:00
abstract::Physical and genetic studies verify that the DNA binding domain of protein gpNu1 (which initiates packaging of phage lambda DNA) is a winged helix-turn-helix (w HTH) and that gpNu1 dimers bind sites that are brought close through DNA bending. ...
journal_title:Molecular cell
pub_type: 评论,杂志文章
doi:10.1016/s1097-2765(02)00536-1
更新日期:2002-05-01 00:00:00
abstract::RING and U-box E3 ubiquitin ligases regulate diverse eukaryotic processes and have been implicated in numerous diseases, but targeting these enzymes remains a major challenge. We report the development of three ubiquitin variants (UbVs), each binding selectively to the RING or U-box domain of a distinct E3 ligase: mon...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2017.09.027
更新日期:2017-10-19 00:00:00
abstract::Serine-arginine (SR) proteins are general splicing factors and can function through binding to exonic splicing enhancers (ESEs). SR proteins and several other mammalian splicing factors contain an arginine-serine-rich (RS) domain required to promote splicing. We have recently found that the ESE bound RS domain functio...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/j.molcel.2004.10.021
更新日期:2004-11-05 00:00:00
abstract::RNA binding proteins (RBPs) regulate all aspects in the life cycle of RNA molecules. To elucidate the elements that guide RNA specificity, regulatory mechanisms, and functions of RBPs, methods that identify direct endogenous protein-RNA interactions are particularly valuable. UV crosslinking and immunoprecipitation (C...
journal_title:Molecular cell
pub_type: 杂志文章,评审
doi:10.1016/j.molcel.2018.01.005
更新日期:2018-02-01 00:00:00
abstract::Protein kinase B/Akt plays crucial roles in promoting cell survival and mediating insulin responses. The enzyme is stimulated by phosphorylation at two regulatory sites: Thr 309 of the activation segment and Ser 474 of the hydrophobic motif, a conserved feature of many AGC kinases. Analysis of the crystal structures o...
journal_title:Molecular cell
pub_type: 杂志文章
doi:10.1016/s1097-2765(02)00550-6
更新日期:2002-06-01 00:00:00