Corrigendium: Effects of RAS on the genesis of embryonal rhabdomyosarcoma [Errata]
(Source: Genes and Development)
Source: Genes and Development - April 17, 2024 Category: Genetics & Stem Cells Authors: Langenau, D. M., Keefe, M. D., Storer, N. Y., Guyon, J. R., Kutok, J. L., Le, X., Goessling, W., Neuberg, D. S., Kunkel, L. M., Zon, L. I. Tags: Errata Source Type: research
Haploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype [Research Papers]
In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR–Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate PDE10A as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expressi...
Source: Genes and Development - April 17, 2024 Category: Genetics & Stem Cells Authors: Nuechterlein, N., Shelbourn, A., Szulzewsky, F., Arora, S., Casad, M., Pattwell, S., Merino-Galan, L., Sulman, E., Arowa, S., Alvinez, N., Jung, M., Brown, D., Tang, K., Jackson, S., Stoica, S., Chittaboina, P., Banasavadi-Siddegowda, Y. K., Wirsching, H. Tags: Research Papers Source Type: research
A germline point mutation in the MYC-FBW7 phosphodegron initiates hematopoietic malignancies [Research Papers]
Oncogenic activation of MYC in cancers predominantly involves increased transcription rather than coding region mutations. However, MYC-dependent lymphomas frequently acquire point mutations in the MYC phosphodegron, including at threonine 58 (T58), where phosphorylation permits binding via the FBW7 ubiquitin ligase triggering MYC degradation. To understand how T58 phosphorylation functions in normal cell physiology, we introduced an alanine mutation at T58 (T58A) into the endogenous c-Myc locus in the mouse germline. While MYC-T58A mice develop normally, lymphomas and myeloid leukemias emerge in ~60% of adult homozygous T...
Source: Genes and Development - April 17, 2024 Category: Genetics & Stem Cells Authors: Freie, B., Carroll, P. A., Varnum-Finney, B. J., Ramsey, E. L., Ramani, V., Bernstein, I., Eisenman, R. N. Tags: Research Papers Source Type: research
NFATC2IP is a mediator of SUMO-dependent genome integrity [Research Papers]
The post-translational modification of proteins by SUMO is crucial for cellular viability and mammalian development in part due to the contribution of SUMOylation to genome duplication and repair. To investigate the mechanisms underpinning the essential function of SUMO, we undertook a genome-scale CRISPR/Cas9 screen probing the response to SUMOylation inhibition. This effort identified 130 genes whose disruption reduces or enhances the toxicity of TAK-981, a clinical-stage inhibitor of the SUMO E1-activating enzyme. Among the strongest hits, we validated and characterized NFATC2IP, an evolutionarily conserved protein rela...
Source: Genes and Development - April 17, 2024 Category: Genetics & Stem Cells Authors: Cho, T., Hoeg, L., Setiaputra, D., Durocher, D. Tags: Research Papers Source Type: research
WRN exonuclease imparts high fidelity on translesion synthesis by Y family DNA polymerases [Research Papers]
Purified translesion synthesis (TLS) DNA polymerases (Pols) replicate through DNA lesions with a low fidelity; however, TLS operates in a predominantly error-free manner in normal human cells. To explain this incongruity, here we determine whether Y family Pols, which play an eminent role in replication through a diversity of DNA lesions, are incorporated into a multiprotein ensemble and whether the intrinsically high error rate of the TLS Pol is ameliorated by the components in the ensemble. To this end, we provide evidence for an indispensable role of Werner syndrome protein (WRN) and WRN-interacting protein 1 (WRNIP1) i...
Source: Genes and Development - April 17, 2024 Category: Genetics & Stem Cells Authors: Yoon, J.-H., Sellamuthu, K., Prakash, L., Prakash, S. Tags: Research Papers Source Type: research
Protein domains of low sequence complexity--dark matter of the proteome [Perspectives]
This perspective begins with a speculative consideration of the properties of the earliest proteins to appear during evolution. What did these primitive proteins look like, and how were they of benefit to early forms of life? I proceed to hypothesize that primitive proteins have been preserved through evolution and now serve diverse functions important to the dynamics of cell morphology and biological regulation. The primitive nature of these modern proteins is easy to spot. They are composed of a limited subset of the 20 amino acids used by traditionally evolved proteins and thus are of low sequence complexity. This chemi...
Source: Genes and Development - April 17, 2024 Category: Genetics & Stem Cells Authors: McKnight, S. L. Tags: Cell Biology Perspectives Source Type: research
Coordination of histone chaperones for parental histone segregation and epigenetic inheritance [Research Papers]
Chromatin-based epigenetic memory relies on the accurate distribution of parental histone H3–H4 tetramers to newly replicated DNA strands. Mcm2, a subunit of the replicative helicase, and Dpb3/4, subunits of DNA polymerase , govern parental histone H3–H4 deposition to the lagging and leading strands, respectively. However, their contribution to epigenetic inheritance remains controversial. Here, using fission yeast heterochromatin inheritance systems that eliminate interference from initiation pathways, we show that a Mcm2 histone binding mutation severely disrupts heterochromatin inheritance, while mutations i...
Source: Genes and Development - March 22, 2024 Category: Genetics & Stem Cells Authors: Fang, Y., Hua, X., Shan, C.-M., Toda, T., Qiao, F., Zhang, Z., Jia, S. Tags: Research Papers Source Type: research
ADNP modulates SINE B2-derived CTCF-binding sites during blastocyst formation in mice [Research Papers]
In this study, we used CUT&RUN technology to investigate CTCF occupancy in mouse preimplantation development. Our findings revealed that CTCF begins binding to the genome prior to zygotic genome activation (ZGA), with a preference for CTCF-anchored chromatin loops. Although the majority of CTCF occupancy is consistently maintained, we identified a specific set of binding sites enriched in the mouse-specific short interspersed element (SINE) family B2 that are restricted to the cleavage stages. Notably, we discovered that the neuroprotective protein ADNP counteracts the stable association of CTCF at SINE B2-derived CTCF...
Source: Genes and Development - March 22, 2024 Category: Genetics & Stem Cells Authors: Wang, W., Gao, R., Yang, D., Ma, M., Zang, R., Wang, X., Chen, C., Kou, X., Zhao, Y., Chen, J., Liu, X., Lu, J., Xu, B., Liu, J., Huang, Y., Chen, C., Wang, H., Gao, S., Zhang, Y., Gao, Y. Tags: Research Papers Source Type: research
Psat1-generated {alpha}-ketoglutarate and glutamine promote muscle stem cell activation and regeneration [Research Papers]
By satisfying bioenergetic demands, generating biomass, and providing metabolites serving as cofactors for chromatin modifiers, metabolism regulates adult stem cell biology. Here, we report that a branch of glycolysis, the serine biosynthesis pathway (SBP), is activated in regenerating muscle stem cells (MuSCs). Gene inactivation and metabolomics revealed that Psat1, one of the three SBP enzymes, controls MuSC activation and expansion of myogenic progenitors through production of the metabolite α-ketoglutarate (α-KG) and α-KG-generated glutamine. Psat1 ablation resulted in defective expansion of MuSCs and...
Source: Genes and Development - March 22, 2024 Category: Genetics & Stem Cells Authors: Ciuffoli, V., Feng, X., Jiang, K., Acevedo-Luna, N., Ko, K. D., Wang, A. H. J., Riparini, G., Khateb, M., Glancy, B., Dell'Orso, S., Sartorelli, V. Tags: Research Papers Source Type: research
A maternal-effect Padi6 variant causes nuclear and cytoplasmic abnormalities in oocytes, as well as failure of epigenetic reprogramming and zygotic genome activation in embryos [Research Papers]
Maternal inactivation of genes encoding components of the subcortical maternal complex (SCMC) and its associated member, PADI6, generally results in early embryo lethality. In humans, SCMC gene variants were found in the healthy mothers of children affected by multilocus imprinting disturbances (MLID). However, how the SCMC controls the DNA methylation required to regulate imprinting remains poorly defined. We generated a mouse line carrying a Padi6 missense variant that was identified in a family with Beckwith–Wiedemann syndrome and MLID. If homozygous in female mice, this variant resulted in interruption of embryo ...
Source: Genes and Development - March 22, 2024 Category: Genetics & Stem Cells Authors: Giaccari, C., Cecere, F., Argenziano, L., Pagano, A., Galvao, A., Acampora, D., Rossi, G., Hay Mele, B., Acurzio, B., Coonrod, S., Cubellis, M. V., Cerrato, F., Andrews, S., Cecconi, S., Kelsey, G., Riccio, A. Tags: Research Papers Source Type: research
ATF7IP2/MCAF2 directs H3K9 methylation and meiotic gene regulation in the male germline [Research Papers]
H3K9 trimethylation (H3K9me3) plays emerging roles in gene regulation, beyond its accumulation on pericentric constitutive heterochromatin. It remains a mystery why and how H3K9me3 undergoes dynamic regulation in male meiosis. Here, we identify a novel, critical regulator of H3K9 methylation and spermatogenic heterochromatin organization: the germline-specific protein ATF7IP2 (MCAF2). We show that in male meiosis, ATF7IP2 amasses on autosomal and X-pericentric heterochromatin, spreads through the entirety of the sex chromosomes, and accumulates on thousands of autosomal promoters and retrotransposon loci. On the sex chromo...
Source: Genes and Development - March 22, 2024 Category: Genetics & Stem Cells Authors: Alavattam, K. G., Esparza, J. M., Hu, M., Shimada, R., Kohrs, A. R., Abe, H., Munakata, Y., Otsuka, K., Yoshimura, S., Kitamura, Y., Yeh, Y.-H., Hu, Y.-C., Kim, J., Andreassen, P. R., Ishiguro, K.-i., Namekawa, S. H. Tags: Research Papers Source Type: research
Pan-cellular organelles and suborganelles--from common functions to cellular diversity? [Reviews]
Cell diversification is at the base of increasing multicellular organism complexity in phylogeny achieved during ontogeny. However, there are also functions common to all cells, such as cell division, cell migration, translation, endocytosis, exocytosis, etc. Here we revisit the organelles involved in such common functions, reviewing recent evidence of unexpected differences of proteins at these organelles. For instance, centrosomes or mitochondria differ significantly in their protein composition in different, sometimes closely related, cell types. This has relevance for development and disease. Particularly striking is t...
Source: Genes and Development - March 22, 2024 Category: Genetics & Stem Cells Authors: Schieweck, R., Götz, M. Tags: Cell Biology Reviews Source Type: research
A serine metabolic enzyme is flexing its muscle to help repair skeletal muscle [Outlook]
Metabolic reprogramming of stem cells is a targetable pathway to control regeneration. Activation of stem cells results in down-regulation of oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) and turns on glycolysis to provide fuel for proliferation and specific signaling events. How cell type-specific events are regulated is unknown. In this issue of Genes & Development Ciuffoli and colleagues (pp. 151–167) use metabolomic, gene inactivation, and functional approaches to show that phosphoserine aminotransferase (Psat1), an enzyme in serine biosynthesis, is activated in muscle stem cells and contr...
Source: Genes and Development - March 22, 2024 Category: Genetics & Stem Cells Authors: Barath, B. R., Nagy, L. Tags: Molecular Physiology and Metabolism Outlook Source Type: research
DNA damage remodels the MITF interactome to increase melanoma genomic instability [Research Papers]
Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA damage response (DDR) programs. However, some cells (for example, in skin) are normally exposed to high levels of DNA-damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown. Using melanoma as a model, we show here that the microphthalmia-associated transcription factor MITF, a lineage addition oncogene that coordinates many aspects of melanocyte and melanoma biology, plays a nontranscriptional role in shaping the ...
Source: Genes and Development - February 13, 2024 Category: Genetics & Stem Cells Authors: Binet, R., Lambert, J.-P., Tomkova, M., Tischfield, S., Baggiolini, A., Picaud, S., Sarkar, S., Louphrasitthiphol, P., Dias, D., Carreira, S., Humphrey, T. C., Fillipakopoulos, P., White, R., Goding, C. R. Tags: Research Papers Source Type: research
Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma [Research Papers]
Approximately 20% of head and neck squamous cell carcinomas (HNSCCs) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M can be divided into two groups: those that display aberrant accumulation of H3K27me3 and those that maintain steady levels of H3K27me3. The former group exhibits reduced proliferation, genome instability, and heightened sensitivity to genotoxi...
Source: Genes and Development - February 13, 2024 Category: Genetics & Stem Cells Authors: Caeiro, L. D., Nakata, Y., Borges, R. L., Zha, M., Garcia-Martinez, L., Banuelos, C. P., Stransky, S., Liu, T., Chan, H. L., Brabson, J., Dominguez, D., Zhang, Y., Lewis, P. W., Aznar Benitah, S., Cimmino, L., Bilbao, D., Sidoli, S., Wang, Z., Verdun, R. Tags: Research Papers Source Type: research
