| 91. |
- Singh, Abeer Prakash, 1988, et al.
(författare)
-
Molecular Connectivity of Mitochondrial Gene Expression and OXPHOS Biogenesis
- 2020
-
Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 79:6
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondria contain their own gene expression systems, including membrane-bound ribosomes dedicated to synthesizing a few hydrophobic subunits of the oxidative phosphorylation (OXPHOS) complexes. We used a proximity-dependent biotinylation technique, BiolD, coupled with mass spectrometry to delineate in baker's yeast a comprehensive network of factors involved in biogenesis of mitochondrial encoded proteins. This mitochondrial gene expression network (MiGENet) encompasses proteins involved in transcription, RNA processing, translation, or protein biogenesis. Our analyses indicate the spatial organization of these processes, thereby revealing basic mechanistic principles and the proteins populating strategically important sites. For example, newly synthesized proteins are directly handed over to ribosomal tunnel exit-bound factors that mediate membrane insertion, co-factor acquisition, or their mounting into OXPHOS complexes in a special early assembly hub. Collectively, the data reveal the connectivity of mitochondrial gene expression, reflecting a unique tailoring of the mitochondrial gene expression system.
|
|
| 92. |
- Sparks, Justin L, et al.
(författare)
-
RNase H2-Initiated Ribonucleotide Excision Repair
- 2012
-
Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 47:6, s. 980-986
-
Tidskriftsartikel (refereegranskat)abstract
- Ribonucleotides are incorporated into DNA by the replicative DNA polymerases at frequencies of about 2 per kb, which makes them by far the most abundant form of potential DNA damage in the cell. Their removal is essential for restoring a stable intact chromosome. Here, we present a complete biochemical reconstitution of the ribonucleotide excision repair (RER) pathway with enzymes purified from Saccharomyces cerevisiae. RER is most efficient when the ribonucleotide is incised by RNase H2, and further excised by the flap endonuclease FEN1 with strand displacement synthesis carried out by DNA polymerase δ, the PCNA clamp, its loader RFC, and completed by DNA ligase I. We observed partial redundancy for several of the enzymes in this pathway. Exo1 substitutes for FEN1 and Pol ε for Pol δ with reasonable efficiency. However, RNase H1 fails to substitute for RNase H2 in the incision step of RER.
|
|
| 93. |
- Stender, Joshua D, et al.
(författare)
-
Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells
- 2017
-
Ingår i: Molecular Cell. - Cambridge, United States : Cell Press. - 1097-2765 .- 1097-4164. ; 65:6, s. 1122-1135.e5
-
Tidskriftsartikel (refereegranskat)abstract
- Human breast cancers that exhibit high proportions of immune cells and elevated levels of pro-inflammatory cytokines predict poor prognosis. Here, we demonstrate that treatment of human MCF-7 breast cancer cells with pro-inflammatory cytokines results in ERα-dependent activation of gene expression and proliferation, in the absence of ligand or presence of 4OH-tamoxifen (TOT). Cytokine activation of ERα and endocrine resistance is dependent on phosphorylation of ERα at S305 in the hinge domain. Phosphorylation of S305 by IKKβ establishes an ERα cistrome that substantially overlaps with the estradiol (E2)-dependent ERα cistrome. Structural analyses suggest that S305-P forms a charge-linked bridge with the C-terminal F domain of ERα that enables inter-domain communication and constitutive activity from the N-terminal coactivator-binding site, revealing the structural basis of endocrine resistance. ERα therefore functions as a transcriptional effector of cytokine-induced IKKβ signaling, suggesting a mechanism through which the tumor microenvironment controls tumor progression and endocrine resistance.
|
|
| 94. |
- Sternberg, Samuel H, et al.
(författare)
-
Adaptation in CRISPR-Cas Systems
- 2016
-
Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 61:6, s. 797-808
-
Tidskriftsartikel (refereegranskat)abstract
- Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins constitute an adaptive immune system in prokaryotes. The system preserves memories of prior infections by integrating short segments of foreign DNA, termed spacers, into the CRISPR array in a process termed adaptation. During the past 3 years, significant progress has been made on the genetic requirements and molecular mechanisms of adaptation. Here we review these recent advances, with a focus on the experimental approaches that have been developed, the insights they generated, and a proposed mechanism for self- versus non-self-discrimination during the process of spacer selection. We further describe the regulation of adaptation and the protein players involved in this fascinating process that allows bacteria and archaea to harbor adaptive immunity.
|
|
| 95. |
|
|
| 96. |
- Trobro, Stefan, et al.
(författare)
-
A Model for How Ribosomal Release Factors Induce Peptidyl-tRNA Cleavage in Termination of Protein Synthesis
- 2007
-
Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 27:5, s. 758-766
-
Tidskriftsartikel (refereegranskat)abstract
- A major unresolved question in messenger RNA translation is how ribosomal release factors terminate protein synthesis. Class 1 release factors decode stop codons and trigger hydrolysis of the bond between the nascent polypeptide and tRNA some 75 Å away from the decoding site. While the gross features of the release factor-ribosome interaction have been revealed by low-resolution crystal structures, there is no information on the atomic level at either the decoding or peptidyl transfer center. We used extensive computer simulations, constrained by experimental data, to predict how bacterial release factors induce peptide dissociation from the ribosome. A distinct structural solution is presented for how the methylated Gln residue of the universally conserved GGQ release factor motif inserts into the ribosomal A site and promotes rapid reaction with the peptidyl-tRNA substrate. This model explains key mutation experiments and shows that the ribosomal peptidyl transfer center catalyzes its two chemical reactions by a common mechanism.
|
|
| 97. |
- Tyagi, Shweta, et al.
(författare)
-
E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases.
- 2007
-
Ingår i: Molecular Cell. - : Elsevier (Cell Press). - 1097-2765 .- 1097-4164. ; 27:1, s. 107-119
-
Tidskriftsartikel (refereegranskat)abstract
- E2F transcriptional regulators control human-cell proliferation by repressing and activating the transcription of genes required for cell-cycle progression, particularly the S phase. E2F proteins repress transcription in association with retinoblastoma pocket proteins, but less is known about how they activate transcription. Here, we show that the human G1 phase regulator HCF-1 associates with both activator (E2F1 and E2F3a) and repressor (E2F4) E2F proteins, properties that are conserved in insect cells. Human HCF-1-E2F interactions are versatile: their associations and binding to E2F-responsive promoters are cell-cycle selective, and HCF-1 displays coactivator properties when bound to the E2F1 activator and corepressor properties when bound to the E2F4 repressor. During the G1-to-S phase transition, HCF-1 recruits the mixed-lineage leukemia (MLL) and Set-1 histone H3 lysine 4 methyltransferases to E2F-responsive promoters and induces histone methylation and transcriptional activation. These results suggest that HCF-1 induces cell-cycle-specific transcriptional activation by E2F proteins to promote cell proliferation.
|
|
| 98. |
- Ueki, Yumi, et al.
(författare)
-
A Consensus Binding Motif for the PP4 Protein Phosphatase
- 2019
-
Ingår i: Molecular Cell. - : CELL PRESS. - 1097-2765 .- 1097-4164. ; 76:6, s. 953-964.e6
-
Tidskriftsartikel (refereegranskat)abstract
- Dynamic protein phosphorylation constitutes a fundamental regulatory mechanism in all organisms. Phosphoprotein phosphatase 4 (PP4) is a conserved and essential nuclear serine and threonine phosphatase. Despite the importance of PP4, general principles of substrate selection are unknown, hampering the study of signal regulation by this phosphatase. Here, we identify and thoroughly characterize a general PP4 consensus-binding motif, the FxxP motif. X-ray crystallography studies reveal that FxxP motifs bind to a conserved pocket in the PP4 regulatory subunit PPP4R3. Systems-wide in silico searches integrated with proteomic analysis of PP4 interacting proteins allow us to identify numerous FxxP motifs in proteins controlling a range of fundamental cellular processes. We identify an FxxP motif in the cohesin release factor WAPL and show that this regulates WAPL phosphorylation status and is required for efficient cohesin release. Collectively our work uncovers basic principles of PP4 specificity with broad implications for understanding phosphorylation-mediated signaling in cells.
|
|
| 99. |
|
|
| 100. |
- Vihervaara, Anniina, et al.
(författare)
-
Stress-induced transcriptional memory accelerates promoter-proximal pause release and decelerates termination over mitotic divisions
- 2021
-
Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 81:8, s. 1715-
-
Tidskriftsartikel (refereegranskat)abstract
- Heat shock instantly reprograms transcription. Whether gene and enhancer transcription fully recover from stress and whether stress establishes a memory by provoking transcription regulation that persists through mitosis remained unknown. Here, we measured nascent transcription and chromatin accessibility in unconditioned cells and in the daughters of stress-exposed cells. Tracking transcription genome-wide at nucleotide-resolution revealed that cells precisely restored RNA polymerase II (Pol II) distribution at gene bodies and enhancers upon recovery from stress. However, a single heat exposure in embryonic fibroblasts primed a faster gene induction in their daughter cells by increasing promoter-proximal Pol II pausing and by accelerating the pause release. In K562 erythroleukemia cells, repeated stress refined basal and heat-induced transcription over mitotic division and decelerated termination-coupled pre-mRNA processing. The slower termination retained transcripts on the chromatin and reduced recycling of Pol II. These results demonstrate that heat-induced transcriptional memory acts through promoter-proximal pause release and pre-mRNA processing at transcription termination.
|
|
