Restrictor synergizes with Symplekin and PNUTS to terminate extragenic transcription [Research Papers]
Transcription termination pathways mitigate the detrimental consequences of unscheduled promiscuous initiation occurring at hundreds of thousands of genomic cis-regulatory elements. The Restrictor complex, composed of the Pol II-interacting protein WDR82 and the RNA-binding protein ZC3H4, suppresses processive transcription at thousands of extragenic sites in mammalian genomes. Restrictor-driven termination does not involve nascent RNA cleavage, and its interplay with other termination machineries is unclear. Here we show that efficient termination at Restrictor-controlled extragenic transcription units involves the recrui...
Source: Genes and Development - December 26, 2023 Category: Genetics & Stem Cells Authors: Russo, M., Piccolo, V., Polizzese, D., Prosperini, E., Borriero, C., Polletti, S., Bedin, F., Marenda, M., Michieletto, D., Mandana, G. M., Rodighiero, S., Cuomo, A., Natoli, G. Tags: Research Papers Source Type: research

The steroid hormone ADIOL promotes learning by reducing neural kynurenic acid levels [Research Papers]
Reductions in brain kynurenic acid levels, a neuroinhibitory metabolite, improve cognitive function in diverse organisms. Thus, modulation of kynurenic acid levels is thought to have therapeutic potential in a range of brain disorders. Here we report that the steroid 5-androstene 3β, 17β-diol (ADIOL) reduces kynurenic acid levels and promotes associative learning in Caenorhabditis elegans. We identify the molecular mechanisms through which ADIOL links peripheral metabolic pathways to neural mechanisms of learning capacity. Moreover, we show that in aged animals, which normally experience rapid cognitive decline, ...
Source: Genes and Development - December 26, 2023 Category: Genetics & Stem Cells Authors: Lemieux, G. A., Yoo, S., Lin, L., Vohra, M., Ashrafi, K. Tags: Research Papers Source Type: research

Molecular basis for PHF7-mediated ubiquitination of histone H3 [Research Papers]
The RING-type E3 ligase has been known for over two decades, yet its diverse modes of action are still the subject of active research. Plant homeodomain (PHD) finger protein 7 (PHF7) is a RING-type E3 ubiquitin ligase responsible for histone ubiquitination. PHF7 comprises three zinc finger domains: an extended PHD (ePHD), a RING domain, and a PHD. While the function of the RING domain is largely understood, the roles of the other two domains in E3 ligase activity remain elusive. Here, we present the crystal structure of PHF7 in complex with the E2 ubiquitin-conjugating enzyme (E2). Our structure shows that E2 is effectivel...
Source: Genes and Development - December 26, 2023 Category: Genetics & Stem Cells Authors: Lee, H. S., Bang, I., You, J., Jeong, T.-K., Kim, C. R., Hwang, M., Kim, J.-S., Baek, S. H., Song, J.-J., Choi, H.-J. Tags: Research Papers Source Type: research

Characterization of the SF3B1-SUGP1 interface reveals how numerous cancer mutations cause mRNA missplicing [Research Papers]
The spliceosomal gene SF3B1 is frequently mutated in cancer. While it is known that SF3B1 hotspot mutations lead to loss of splicing factor SUGP1 from spliceosomes, the cancer-relevant SF3B1–SUGP1 interaction has not been characterized. To address this issue, we show by structural modeling that two regions flanking the SUGP1 G-patch make numerous contacts with the region of SF3B1 harboring hotspot mutations. Experiments confirmed that all the cancer-associated mutations in these regions, as well as mutations affecting other residues in the SF3B1–SUGP1 interface, not only weaken or disrupt the interaction but al...
Source: Genes and Development - December 26, 2023 Category: Genetics & Stem Cells Authors: Zhang, J., Xie, J., Huang, J., Liu, X., Xu, R., Tholen, J., Galej, W. P., Tong, L., Manley, J. L., Liu, Z. Tags: Research Papers Source Type: research

LINE-1 retrotransposition and its deregulation in cancers: implications for therapeutic opportunities [Reviews]
Long interspersed element 1 (LINE-1) is the only protein-coding transposon that is active in humans. LINE-1 propagates in the genome using RNA intermediates via retrotransposition. This activity has resulted in LINE-1 sequences occupying approximately one-fifth of our genome. Although most copies of LINE-1 are immobile, ~100 copies are retrotransposition-competent. Retrotransposition is normally limited via epigenetic silencing, DNA repair, and other host defense mechanisms. In contrast, LINE-1 overexpression and retrotransposition are hallmarks of cancers. Here, we review mechanisms of LINE-1 regulation and how LINE-1 may...
Source: Genes and Development - December 26, 2023 Category: Genetics & Stem Cells Authors: Mendez-Dorantes, C., Burns, K. H. Tags: Chromatin and Gene Expression, Cancer and Disease Models Reviews Source Type: research

AI-assisted proofreading of RNA splicing [Outlook]
RNA helicases orchestrate proofreading mechanisms that facilitate accurate intron removal from pre-mRNAs. How these activities are recruited to spliceosome/pre-mRNA complexes remains poorly understood. In this issue of Genes & Development, Zhang and colleagues (pp. 968–983) combine biochemical experiments with AI-based structure prediction methods to generate a model for the interaction between SF3B1, a core splicing factor essential for the recognition of the intron branchpoint, and SUGP1, a protein that bridges SF3B1 with the helicase DHX15. Interaction with SF3B1 exposes the G-patch domain of SUGP1, facilitati...
Source: Genes and Development - December 26, 2023 Category: Genetics & Stem Cells Authors: Guerra-Moreno, A., Valcarcel, J. Tags: Chromatin and Gene Expression, Post-transcriptional Control Outlook Source Type: research

ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy [Research Papers]
The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target MMR-d cancer cells. Here, we show that inhibition of the ATR kinase preferentially kills MMR-d cancer cells. Mechanistically, ATR inhibitor (ATRi) imposes synthetic lethality on MMR-d cells by inducing DNA damage in a replication- and MUS81 nuclease-dependent manner. The DNA damage induced by ATRi is colocalized with both MSH2 and PCNA, suggesting that it arises from DNA ...
Source: Genes and Development - November 13, 2023 Category: Genetics & Stem Cells Authors: Wang, M., Ran, X., Leung, W., Kawale, A., Saxena, S., Ouyang, J., Patel, P. S., Dong, Y., Yin, T., Shu, J., Manguso, R. T., Lan, L., Wang, X.-F., Lawrence, M. S., Zou, L. Tags: Research Papers Source Type: research

Comprehensive mapping of cell fates in microsatellite unstable cancer cells supports dual targeting of WRN and ATR [Research Papers]
Addiction to the WRN helicase is a unique vulnerability of human cancers with high levels of microsatellite instability (MSI-H). However, while prolonged loss of WRN ultimately leads to cell death, little is known about how MSI-H cancers initially respond to acute loss of WRN—knowledge that would be helpful for informing clinical development of WRN targeting therapy, predicting possible resistance mechanisms, and identifying useful biomarkers of successful WRN inhibition. Here, we report the construction of an inducible ligand-mediated degradation system in which the stability of endogenous WRN protein can be rapidly...
Source: Genes and Development - November 13, 2023 Category: Genetics & Stem Cells Authors: Zong, D., Koussa, N. C., Cornwell, J. A., Pankajam, A. V., Kruhlak, M. J., Wong, N., Chari, R., Cappell, S. D., Nussenzweig, A. Tags: Research Papers Source Type: research

Reorganization of lamina-associated domains in early mouse embryos is regulated by RNA polymerase II activity [Research Papers]
We report that LADs reorganize gradually in two-cell embryos and that blocking ZGA leads to major changes in nuclear organization, including altered chromatin and genomic features of LADs and redistribution of H3K4me3 toward the nuclear lamina. Our data indicate that the rearrangement of LADs is an integral component of the maternal-to-zygotic transition and that transcription contributes to shaping nuclear organization at the beginning of mammalian development. (Source: Genes and Development)
Source: Genes and Development - November 13, 2023 Category: Genetics & Stem Cells Authors: Pal, M., Altamirano-Pacheco, L., Schauer, T., Torres-Padilla, M.-E. Tags: Research Papers Source Type: research

A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels [Research Papers]
Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G>A, p.Gly118Glu [G118E]), which has never been seen before in MECP2, in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant caused the clinical symptoms and study its functional consequences, we established two disease models, including human neurons from patient-derived...
Source: Genes and Development - November 13, 2023 Category: Genetics & Stem Cells Authors: Zhou, J., Cattoglio, C., Shao, Y., Tirumala, H. P., Vetralla, C., Bajikar, S. S., Li, Y., Chen, H., Wang, Q., Wu, Z., Tang, B., Zahabiyon, M., Bajic, A., Meng, X., Ferrie, J. J., LaGrone, A., Zhang, P., Kim, J. J., Tang, J., Liu, Z., Darzacq, X., Heintz, Tags: Research Papers Source Type: research

MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival [Research Papers]
The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and the functions of specific acetylated lysine (AcK) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various malignant and nonmalignant cells. Oncogenic overexpression of MYC enhances its acetylation and alters the regulation of site-specific acetylation by proteasome and deacetylase inhibitors. Acetylation of MYC at different K residu...
Source: Genes and Development - November 13, 2023 Category: Genetics & Stem Cells Authors: Hurd, M., Pino, J., Jang, K., Allevato, M. M., Vorontchikhina, M., Ichikawa, W., Zhao, Y., Gates, R., Villalpando, E., Hamilton, M. J., Faiola, F., Pan, S., Qi, Y., Hung, Y.-W., Girke, T., Ann, D., Seewaldt, V., Martinez, E. Tags: Research Papers Source Type: research

Imaging the binding of MECP2 to DNA [Outlook]
Mutations in the methyl-DNA binding domain of MECP2 cause Rett syndrome; however, distinct mutations are associated with different severity of the disease. Live-cell imaging and single-molecule tracking are sensitive methods to quantify the DNA binding affinity and diffusion dynamics of nuclear proteins. In this issue of Genes & Development, Zhou and colleagues (pp. 883–900) used these imaging methods to quantitatively describe the partial loss of DNA binding resulting from a novel pathological MECP2 mutation with intermediate disease severity. These data demonstrate how single-molecule tracking can advance under...
Source: Genes and Development - November 13, 2023 Category: Genetics & Stem Cells Authors: West, A. E. Tags: Development, Chromatin and Gene Expression, Neurobiology Outlook Source Type: research

Corrigendum: The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells [Errata]
(Source: Genes and Development)
Source: Genes and Development - October 18, 2023 Category: Genetics & Stem Cells Authors: Bracken, A. P., Kleine-Kohlbrecher, D., Dietrich, N., Pasini, D., Gargiulo, G., Beekman, C., Theilgaard-Mönch, K., Minucci, S., Porse, B. T., Marine, J.-C., Hansen, K. H., Helin, K. Tags: Errata Source Type: research

In vitro reconstitution of SARS-CoV-2 Nsp1-induced mRNA cleavage reveals the key roles of the N-terminal domain of Nsp1 and the RRM domain of eIF3g [Research Papers]
SARS CoV-2 nonstructural protein 1 (Nsp1) is the major pathogenesis factor that inhibits host translation using a dual strategy of impairing initiation and inducing endonucleolytic cleavage of cellular mRNAs. To investigate the mechanism of cleavage, we reconstituted it in vitro on β-globin, EMCV IRES, and CrPV IRES mRNAs that use unrelated initiation mechanisms. In all instances, cleavage required Nsp1 and only canonical translational components (40S subunits and initiation factors), arguing against involvement of a putative cellular RNA endonuclease. Requirements for initiation factors differed for these mRNAs, refl...
Source: Genes and Development - October 18, 2023 Category: Genetics & Stem Cells Authors: Abaeva, I. S., Arhab, Y., Miscicka, A., Hellen, C. U. T., Pestova, T. V. Tags: Research Papers Source Type: research

Allelic chromatin structure precedes imprinted expression of Kcnk9 during neurogenesis [Research Papers]
Differences in chromatin state inherited from the parental gametes influence the regulation of maternal and paternal alleles in offspring. This phenomenon, known as genomic imprinting, results in genes preferentially transcribed from one parental allele. While local epigenetic factors such as DNA methylation are known to be important for the establishment of imprinted gene expression, less is known about the mechanisms by which differentially methylated regions (DMRs) lead to differences in allelic expression across broad stretches of chromatin. Allele-specific higher-order chromatin structure has been observed at multiple...
Source: Genes and Development - October 18, 2023 Category: Genetics & Stem Cells Authors: Loftus, D., Bae, B., Whilden, C. M., Whipple, A. J. Tags: Research Papers Source Type: research