bims-dresag Biomed News
on DNA damage and repair, cellular senescence and aging, gene therapy
Issue of 2021–06–27
nine papers selected by
Pengyi Yan, Shanghai Jiao Tong University
  1. Treacle TOPBP1 into nuclei to handle ribosomal-DNA replication stress.
  2. Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop.
  3. The redox-senescence axis and its therapeutic targeting.
  4. REV7 directs DNA repair pathway choice.
  5. Using CRISPR to understand how cancer mutations happen.
  6. CRISPR Interference (CRISPRi) and CRISPR Activation (CRISPRa) to Explore the Oncogenic lncRNA Network.
  7. A Potential Role for Integrin-Linked Kinase in Colorectal Cancer Growth and Progression via Regulating Senescence and Immunity.
  8. Senotherapeutics: Targeting senescent cells for the main age-related diseases.
  9. Identification of autophagy-related genes as targets for senescence induction using a customizable CRISPR-based suicide switch screen.
  1. Nat Rev Mol Cell Biol. 2021 Jun 25.
    Treacle TOPBP1 into nuclei to handle ribosomal-DNA replication stress.
    Eytan Zlotorynski.
      
    DOI:  https://doi.org/10.1038/s41580-021-00393-3
  2. Cell. 2021 Jun 17. pii: S0092-8674(21)00657-7. [Epub ahead of print]
    Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop.
    Francesco Marangoni, Ademi Zhakyp, Michela Corsini, Shannon N Geels, Esteban Carrizosa, Martin Thelen, Vinidhra Mani, Jasper N Prüßmann, Ross D Warner, Aleksandra J Ozga, Mauro Di Pilato, Shivashankar Othy, Thorsten R Mempel.
      Foxp3+ T regulatory (Treg) cells promote immunological tumor tolerance, but how their immune-suppressive function is regulated in the tumor microenvironment (TME) remains unknown. Here, we used intravital microscopy to characterize the cellular interactions that provide tumor-infiltrating Treg cells with critical activation signals. We found that the polyclonal Treg cell repertoire is pre-enriched to recognize antigens presented by tumor-associated conventional dendritic cells (cDCs). Unstable cDC contacts sufficed to sustain Treg cell function, whereas T helper cells were activated during stable interactions. Contact instability resulted from CTLA-4-dependent downregulation of co-stimulatory B7-family proteins on cDCs, mediated by Treg cells themselves. CTLA-4-blockade triggered CD28-dependent Treg cell hyper-proliferation in the TME, and concomitant Treg cell inactivation was required to achieve tumor rejection. Therefore, Treg cells self-regulate through a CTLA-4- and CD28-dependent feedback loop that adjusts their population size to the amount of local co-stimulation. Its disruption through CTLA-4-blockade may off-set therapeutic benefits in cancer patients.
    Keywords:  CD28; CTLA-4; MP-IVM; NFAT; T regulatory cell; Treg cell; cytotoxic T lymphocyte-associated protein 4; multiphoton intravital microscopy; nuclear factor of activated T cells; tumor tolerance
    DOI:  https://doi.org/10.1016/j.cell.2021.05.027
  3. Redox Biol. 2021 Jun 05. pii: S2213-2317(21)00190-7. [Epub ahead of print]45 102032
    The redox-senescence axis and its therapeutic targeting.
    Natalie Yl Ngoi, Angeline Qx Liew, Stephen J F Chong, Matthew S Davids, Marie-Veronique Clement, Shazib Pervaiz.
       SIGNIFICANCE: Cellular growth arrest, associated with 'senescence', helps to safeguard against the accumulation of DNA damage which is often recognized as the underlying mechanism of a wide variety of age-related pathologies including cancer. Cellular senescence has also been described as a 'double-edged sword'. In cancer, for example, the creation of an immune-suppressive milieu by senescent tumor cells through the senescence-associated secretory phenotype contributes toward carcinogenesis and cancer progression.
    RECENT ADVANCES: The potential for cellular senescence to confer multi-faceted effects on tissue fate has led to a rejuvenated interest in its landscape and targeting. Interestingly, redox pathways have been described as both triggers and propagators of cellular senescence, leading to intricate cross-links between both pathways.
    CRITICAL ISSUES: In this review, we describe the mechanisms driving cellular senescence, the interface with cellular redox metabolism as well as the role that chemotherapy-induced senescence plays in secondary carcinogenesis. Notably, the role that anti-apoptotic proteins of the Bcl-2 family play in inducing drug resistance via mechanisms that involve senescence induction.
    FUTURE DIRECTIONS: Though the therapeutic targeting of senescent cells as cancer therapy remains in its infancy, we summarize the current development of senotherapeutics, including recognized senotherapies, as well as the repurposing of drugs as senomorphic/senolytic candidates.
    Keywords:  Cancer therapy; ROS; SASP; Senescence; Senolytics
    DOI:  https://doi.org/10.1016/j.redox.2021.102032
  4. Trends Cell Biol. 2021 Jun 16. pii: S0962-8924(21)00114-8. [Epub ahead of print]
    REV7 directs DNA repair pathway choice.
    Connor S Clairmont, Alan D D'Andrea.
      REV7 is a small multifunctional protein that participates in multiple DNA repair pathways, most notably translesion DNA synthesis and double-strand break (DSB) repair. While the role of REV7 in translesion synthesis has been known for several decades, its function in DSB repair is a recent discovery. Investigations into the DSB repair function of REV7 have led to the discovery of a new DNA repair complex known as Shieldin. Recent studies have also highlighted the importance of REV7's HORMA domain, an ancient structural motif, in REV7 function and have identified the HORMA regulators, TRIP13 and p31, as novel DNA repair factors. In this review, we discuss these recent findings and their implications for repair pathway choice, at both DSBs and replication forks. We suggest that REV7, in particular the activation state of its HORMA domain, can act as a critical determinant of mutagenic versus error-free repair in multiple contexts.
    Keywords:  DNA repair; Fanconi anemia; REV7; Shieldin; TRIP13; double-strand break repair; translesion synthesis
    DOI:  https://doi.org/10.1016/j.tcb.2021.05.009
  5. Commun Biol. 2021 Jun 23. 4(1): 807
    Using CRISPR to understand how cancer mutations happen.
    Eve H Rogers.
      
    DOI:  https://doi.org/10.1038/s42003-021-02313-9
  6. Methods Mol Biol. 2021 ;2348 189-204
    CRISPR Interference (CRISPRi) and CRISPR Activation (CRISPRa) to Explore the Oncogenic lncRNA Network.
    Eugenio Morelli, Annamaria Gulla', Nicola Amodio, Elisa Taiana, Antonino Neri, Mariateresa Fulciniti, Nikhil C Munshi.
      The human genome contains thousands of long noncoding RNAs (lncRNAs), even outnumbering protein-coding genes. These molecules can play a pivotal role in the development and progression of human disease, including cancer, and are susceptible to therapeutic intervention. Evidence of biologic function, however, is still missing for the vast majority of them. Both loss-of-function (LOF) and gain-of-function (GOF) studies are therefore necessary to advance our understanding of lncRNA networks and programs driving tumorigenesis. Here, we describe a protocol to perform lncRNA's LOF or GOF studies in multiple myeloma (MM) cells, using CRISPR interference (CRISPRi) or CRISPR activation (CRISPRa) technologies, respectively. These approaches have many advantages, including applicability to large-scale genetic screens in mammalian cells and possible reversibility of modulating effects; moreover, CRISPRa offers the unique opportunity to enhance lncRNA expression at the site of transcription, with relevant biologic implications.
    Keywords:  CRISPR activation; CRISPR interference; CRISPRa; CRISPRi; Cancer; Long noncoding RNA; Multiple myeloma; lncRNA
    DOI:  https://doi.org/10.1007/978-1-0716-1581-2_13
  7. Front Genet. 2021 ;12 638558
    A Potential Role for Integrin-Linked Kinase in Colorectal Cancer Growth and Progression via Regulating Senescence and Immunity.
    Saleh Almasabi, Afsar U Ahmed, Richard Boyd, Bryan R G Williams.
      Integrin-linked kinase (ILK) has been implicated as a molecular driver and mediator in both inflammation and tumorigenesis of the colon. ILK functions as an adaptor and mediator protein linking the extracellular matrix with downstream signaling pathways. ILK is broadly expressed in many human tissues and cells. It is also overexpressed in many cancers, including colorectal cancer (CRC). Inflammation, as evidenced by inflammatory bowel disease (IBD), is one of the highest risk factors for initiating CRC. This has led to the hypothesis that targeting ILK therapeutically could have potential in CRC, as it regulates different cellular processes associated with CRC development and progression as well as inflammation in the colon. A number of studies have indicated an ILK function in senescence, a cellular process that arrests the cell cycle while maintaining active metabolism and transcription. Senescent cells produce different secretions collectively known as the senescence-associated secretory phenotype (SASP). The SASP secretions influence infiltration of different immune cells, either positively for clearing senescent cells or negatively for promoting tumor growth, reflecting the dual role of senescence in cancer. However, a role for ILK in senescence and immunity in CRC remains to be determined. In this review, we discuss the possible role for ILK in senescence and immunity, paying particular attention to the relevance of ILK in CRC. We also examine how activating Toll-like receptors (TLRs) and their agonists in CRC could trigger immune responses against cancer, as a combination therapy with ILK inhibition.
    Keywords:  colorectal cancer; combination theraoy; immunity; integrin-linked kinase; senescence
    DOI:  https://doi.org/10.3389/fgene.2021.638558
  8. Mech Ageing Dev. 2021 Jun 21. pii: S0047-6374(21)00098-1. [Epub ahead of print]197 111526
    Senotherapeutics: Targeting senescent cells for the main age-related diseases.
    Virginia Boccardi, Patrizia Mecocci.
      The review aims to summarize and discuss the current knowledge on targeting senescent cells to reduce the risk of age-related diseases in animal models and human studies. The role of cellular senescence in aging and the major age-related diseases -including Alzheimer's disease, atherosclerosis, and type 2 diabetes- as well as the use of senotherapeutic strategies in both experimental and preclinical studies, will be described. A large number of molecules, including synthetic agents and natural compounds, have been proposed for anti-senescence activities. Research on senotherapeutics, which includes senolytic and senomorphic, has a growing interest, and their safety and reliability as anti-aging drugs have been tested in clinical trials. Initial findings suggest that the senotherapeutic approach may be translatable to humans. Due to the lack of evidence, caution must be used against senolytic agents due to their potential side-effects. In this context, natural senolytic compounds should have the advantage of low toxicity and potentially more useful in humans, although the mechanisms of action need to be defined.
    Keywords:  Age-related diseases; Aging; Senescence; Senolytic; Senomorphic
    DOI:  https://doi.org/10.1016/j.mad.2021.111526
  9. Mol Cancer Res. 2021 Jun 22. pii: molcanres.0146.2021. [Epub ahead of print]
    Identification of autophagy-related genes as targets for senescence induction using a customizable CRISPR-based suicide switch screen.
    Arnout Schepers, Fleur Jochems, Cor Lieftink, Liqin Wang, Ziva Pogacar, Rodrigo Leite de Oliveira, Giulia De Conti, Roderick L Beijersbergen, Rene Bernards.
      Pro-senescence therapies are increasingly being considered for the treatment of cancer. Identifying additional targets to induce senescence in cancer cells could further enable such therapies. However, screening for targets whose suppression induces senescence on a genome-wide scale is challenging, as senescent cells become growth arrested, and senescence-associated features can take 1-2 weeks to develop. For a screen with a whole-genome CRISPR library, this would result in billions of undesirable proliferating cells by the time the senescent features emerge in the growth arrested cells. Here, we present a suicide switch system that allows genome-wide CRISPR screening in growth-arrested subpopulations by eliminating the proliferating cells during the screen through activation of a suicide switch in proliferating cells. Using this system, we identify in a genome-scale CRISPR screen several autophagy related proteins as targets for senescence induction. We show that inhibiting macroautophagy with a small molecule ULK1 inhibitor can induce senescence in cancer cell lines of different origin. Finally, we show that combining ULK1 inhibition with the senolytic drug ABT-263 leads to apoptosis in a panel of cancer cell lines. Implications: Our suicide switch approach allows for genome-scale identification of pro-senescence targets, and can be adapted to simplify other screens depending on the nature of the promoter used to drive the switch.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-0146
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