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Genes & Development
Journal Prestige (SJR): 10.214
Citation Impact (citeScore): 9
Number of Followers: 38  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0890-9369 - ISSN (Online) 1549-5477
Published by Cold Spring Harbor Lab Press Homepage  [8 journals]
  • Anticipating resistance to KRAS inhibition: a novel role for USP21 in
           macropinocytosis regulation [Outlook]

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      Authors: Crawford; H. C.
      Pages: 1325 - 1326
      Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Virtually all PDAC harbors an oncogenic mutation in the KRAS gene, making it the prime target for therapy. Most previous attempts to inhibit KRAS directly have been disappointing, but recent success in targeting some KRAS mutants presages a new era in PDAC therapy. Models of PDAC have predicted that identifying KRAS inhibitor resistance mechanisms will be critical. In this issue of Genes & Development, Hou and colleagues (pp. 1327–1332) identify one such mechanism in which the deubiquitinase USP21 up-regulates the nutrient-scavenging process of macropinocytosis, rescuing PDAC cells from Kras extinction.
      Keywords: Cancer and Disease Models
      PubDate: 2021-10-01T06:30:21-07:00
      DOI: 10.1101/gad.348971.121
      Issue No: Vol. 35, No. 19-20 (2021)
       
  • USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS
           bypass in pancreatic cancer [Research Communications]

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      Authors: Hou, P; Ma, X, Yang, Z, Zhang, Q, Wu, C.-J, Li, J, Tan, L, Yao, W, Yan, L, Zhou, X, Kimmelman, A. C, Lorenzi, P. L, Zhang, J, Jiang, S, Spring, D, Wang, Y. A, DePinho, R. A.
      Pages: 1327 - 1332
      Abstract: Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.
      PubDate: 2021-10-01T06:30:21-07:00
      DOI: 10.1101/gad.348787.121
      Issue No: Vol. 35, No. 19-20 (2021)
       
  • Cold-responsive adipocyte progenitors couple adrenergic signaling to
           immune cell activation to promote beige adipocyte accrual [Research
           Communications]

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      Authors: Shan, B; Shao, M, Zhang, Q, An, Y. A, Vishvanath, L, Gupta, R. K.
      Pages: 1333 - 1338
      Abstract: The full array of cold-responsive cell types within white adipose tissue that drive thermogenic beige adipocyte biogenesis remains undefined. We demonstrate that acute cold challenge elicits striking transcriptomic changes specifically within DPP4+ PDGFRβ+ adipocyte precursor cells, including a β-adrenergic receptor CREB-mediated induction in the expression of the prothermogenic cytokine, Il33. Doxycycline-inducible deletion of Il33 in PDGFRβ+ cells at the onset of cold exposure attenuates ILC2 accumulation and beige adipocyte accrual. These studies highlight the multifaceted roles for adipocyte progenitors and the ability of select mesenchymal subpopulations to relay neuronal signals to tissue-resident immune cells in order to regulate tissue plasticity.
      PubDate: 2021-10-01T06:30:21-07:00
      DOI: 10.1101/gad.348762.121
      Issue No: Vol. 35, No. 19-20 (2021)
       
  • Disruption of origin chromatin structure by helicase activation in the
           absence of DNA replication [Research Papers]

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      Authors: Hoffman, R. A; MacAlpine, H. K, MacAlpine, D. M.
      Pages: 1339 - 1355
      Abstract: Prior to initiation of DNA replication, the eukaryotic helicase, Mcm2-7, must be activated to unwind DNA at replication start sites in early S phase. To study helicase activation within origin chromatin, we constructed a conditional mutant of the polymerase α subunit Cdc17 (or Pol1) to prevent priming and block replication. Recovery of these cells at permissive conditions resulted in the generation of unreplicated gaps at origins, likely due to helicase activation prior to replication initiation. We used micrococcal nuclease (MNase)-based chromatin occupancy profiling under restrictive conditions to study chromatin dynamics associated with helicase activation. Helicase activation in the absence of DNA replication resulted in the disruption and disorganization of chromatin, which extends up to 1 kb from early, efficient replication origins. The CMG holohelicase complex also moves the same distance out from the origin, producing single-stranded DNA that activates the intra-S-phase checkpoint. Loss of the checkpoint did not regulate the progression and stalling of the CMG complex but rather resulted in the disruption of chromatin at both early and late origins. Finally, we found that the local sequence context regulates helicase progression in the absence of DNA replication, suggesting that the helicase is intrinsically less processive when uncoupled from replication.
      PubDate: 2021-10-01T06:30:21-07:00
      DOI: 10.1101/gad.348517.121
      Issue No: Vol. 35, No. 19-20 (2021)
       
  • Role of 53BP1 in end protection and DNA synthesis at DNA breaks [Research
           Papers]

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      Authors: Paiano, J; Zolnerowich, N, Wu, W, Pavani, R, Wang, C, Li, H, Zheng, L, Shen, B, Sleckman, B. P, Chen, B.-R, Nussenzweig, A.
      Pages: 1356 - 1367
      Abstract: Double-strand break (DSB) repair choice is greatly influenced by the initial processing of DNA ends. 53BP1 limits the formation of recombinogenic single-strand DNA (ssDNA) in BRCA1-deficient cells, leading to defects in homologous recombination (HR). However, the exact mechanisms by which 53BP1 inhibits DSB resection remain unclear. Previous studies have identified two potential pathways: protection against DNA2/EXO1 exonucleases presumably through the Shieldin (SHLD) complex binding to ssDNA, and localized DNA synthesis through the CTC1-STN1-TEN1 (CST) and DNA polymerase α (Polα) to counteract resection. Using a combinatorial approach of END-seq, SAR-seq, and RPA ChIP-seq, we directly assessed the extent of resection, DNA synthesis, and ssDNA, respectively, at restriction enzyme-induced DSBs. We show that, in the presence of 53BP1, Polα-dependent DNA synthesis reduces the fraction of resected DSBs and the resection lengths in G0/G1, supporting a previous model that fill-in synthesis can limit the extent of resection. However, in the absence of 53BP1, Polα activity is sustained on ssDNA yet does not substantially counter resection. In contrast, EXO1 nuclease activity is essential for hyperresection in the absence of 53BP1. Thus, Polα-mediated fill-in partially limits resection in the presence of 53BP1 but cannot counter extensive hyperresection due to the loss of 53BP1 exonuclease blockade. These data provide the first nucleotide mapping of DNA synthesis at resected DSBs and provide insight into the relationship between fill-in polymerases and resection exonucleases.
      PubDate: 2021-10-01T06:30:21-07:00
      DOI: 10.1101/gad.348667.121
      Issue No: Vol. 35, No. 19-20 (2021)
       
  • Vertebrate CTF18 and DDX11 essential function in cohesion is bypassed by
           preventing WAPL-mediated cohesin release [Research Papers]

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      Authors: Kawasumi, R; Abe, T, Psakhye, I, Miyata, K, Hirota, K, Branzei, D.
      Pages: 1368 - 1382
      Abstract: The alternative PCNA loader containing CTF18-DCC1-CTF8 facilitates sister chromatid cohesion (SCC) by poorly defined mechanisms. Here we found that in DT40 cells, CTF18 acts complementarily with the Warsaw breakage syndrome DDX11 helicase in mediating SCC and proliferation. We uncover that the lethality and cohesion defects of ctf18 ddx11 mutants are associated with reduced levels of chromatin-bound cohesin and rescued by depletion of WAPL, a cohesin-removal factor. On the contrary, high levels of ESCO1/2 acetyltransferases that acetylate cohesin to establish SCC do not rescue ctf18 ddx11 phenotypes. Notably, the tight proximity of sister centromeres and increased anaphase bridges characteristic of WAPL-depleted cells are abrogated by loss of both CTF18 and DDX11. The results reveal that vertebrate CTF18 and DDX11 collaborate to provide sufficient amounts of chromatin-loaded cohesin available for SCC generation in the presence of WAPL-mediated cohesin-unloading activity. This process modulates chromosome structure and is essential for cellular proliferation in vertebrates.
      PubDate: 2021-10-01T06:30:21-07:00
      DOI: 10.1101/gad.348581.121
      Issue No: Vol. 35, No. 19-20 (2021)
       
  • Systematic functional characterization of antisense eRNA of protocadherin
           {alpha} composite enhancer [Research Papers]

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      Authors: Zhou, Y; Xu, S, Zhang, M, Wu, Q.
      Pages: 1383 - 1394
      Abstract: Enhancers generate bidirectional noncoding enhancer RNAs (eRNAs) that may regulate gene expression. At present, the eRNA function remains enigmatic. Here, we report a 5' capped antisense eRNA PEARL (Pcdh eRNA associated with R-loop formation) that is transcribed from the protocadherin (Pcdh) α HS5-1 enhancer region. Through loss- and gain-of-function experiments with CRISPR/Cas9 DNA fragment editing, CRISPRi, and CRISPRa, as well as locked nucleic acid strategies, in conjunction with ChIRP, MeDIP, DRIP, QHR-4C, and HiChIP experiments, we found that PEARL regulates Pcdhα gene expression by forming local RNA–DNA duplexes (R-loops) in situ within the HS5-1 enhancer region to promote long-distance chromatin interactions between distal enhancers and target promoters. In particular, increased levels of eRNA PEARL via perturbing transcription elongation factor SPT6 lead to strengthened local three-dimensional chromatin organization within the Pcdh superTAD. These findings have important implications regarding molecular mechanisms by which the HS5-1 enhancer regulates stochastic Pcdhα promoter choice in single cells in the brain.
      PubDate: 2021-10-01T06:30:21-07:00
      DOI: 10.1101/gad.348621.121
      Issue No: Vol. 35, No. 19-20 (2021)
       
 
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