bims-dresag 2021-07-04 papers

bims-dresag

Biomed News

on DNA damage and repair, cellular senescence and aging, gene therapy

Issue of 2021–07–04
six papers selected by
Pengyi Yan, Shanghai Jiao Tong University

The Heritability of Replication Problems.
The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy.
Senescence and Aging: Does It Impact Cancer Immunotherapies?
MYC-Induced Replicative Stress: A Double-Edged Sword for Cancer Development and Treatment.
Luteolin inhibits H2O2-induced cellular senescence via modulation of SIRT1 and p53.
Emerging Therapeutic Potential of SIRT6 Modulators.

Cells. 2021 Jun 11. pii: 1464. [Epub ahead of print]10(6):

The Heritability of Replication Problems.

Jean-Sébastien Hoffmann.

  The major challenge of DNA replication is to provide daughter cells with intact and fully duplicated genetic material. However, various endogenous or environmental factors can slow down or stall DNA replication forks; these replication problems are known to fuel genomic instability and associated pathology, including cancer progression. Whereas the mechanisms emphasizing the source and the cellular responses of replicative problems have attracted much consideration over the past decade, the propagation through mitosis of genome modification and its heritability in daughter cells when the stress is not strong enough to provoke a checkpoint response in G2/M was much less documented. Some recent studies addressing whether low replication stress could impact the DNA replication program of the next generation of cells made the remarkable discovery that DNA damage can indeed be transmitted to daughter cells and can be processed in the subsequent S-phase, and that the replication timing program at a subset of chromosomal domains can also be impacted in the next generation of cells. Such a progression of replication problems into mitosis and daughter cells may appear counter-intuitive, but it could offer considerable advantages by alerting the next generation of cells of potentially risky loci and offering the possibility of an adaptive mechanism to anticipate a reiteration of problems, notably for cancer cells in the context of resistance to therapy.

Keywords:  DNA damage; DNA replication; replication timing; replicative stress

DOI:  https://doi.org/10.3390/cells10061464
Pharmacol Ther. 2021 Jun 25. pii: S0163-7258(21)00145-5. [Epub ahead of print] 107943

The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy.

Alakananda Basu.

  Cell death by apoptosis and permanent cell cycle arrest by senescence serve as barriers to the development of cancer. Chemotherapeutic agents not only induce apoptosis, they can also induce senescence known as therapy-induced senescence (TIS). There are, however, controversies whether TIS improves or worsens therapeutic outcome. Unlike apoptosis, which permanently removes cancer cells, senescent cells are metabolically active, and can contribute to tumor progression and relapse. If senescent cells are not cleared by the immune system or if cancer cells escape senescence, they may acquire resistance to apoptotic stimuli and become highly aggressive. Thus, there have been significant efforts in developing senolytics, drugs that target these pro-survival molecules to eliminate senescent cells. The anti-apoptotic Bcl-2 family proteins not only protect against cell death by apoptosis, but they also allow senescent cells to survive. While combining senolytics with chemotherapeutic drugs is an attractive approach, there are also limitations. Moreover, members of the Bcl-2 family have distinct effects on apoptosis and senescence. The purpose of this review article is to discuss recent literatures on how members of the Bcl-2 family orchestrate the interplay between apoptosis and senescence, and the challenges and progress in targeting these Bcl-2 family proteins for cancer therapy.

Keywords:  Apoptosis; Bcl-2; Bcl-xl Mcl-1; Senescence; Senolytics

DOI:  https://doi.org/10.1016/j.pharmthera.2021.107943
Cells. 2021 Jun 22. pii: 1568. [Epub ahead of print]10(7):

Senescence and Aging: Does It Impact Cancer Immunotherapies?

Damien Maggiorani, Christian Beauséjour.

  Cancer incidence increases drastically with age. Of the many possible reasons for this, there is the accumulation of senescent cells in tissues and the loss of function and proliferation potential of immune cells, often referred to as immuno-senescence. Immune checkpoint inhibitors (ICI), by invigorating immune cells, have the potential to be a game-changers in the treatment of cancer. Yet, the variability in the efficacy of ICI across patients and cancer types suggests that several factors influence the success of such inhibitors. There is currently a lack of clinical studies measuring the impact of aging and senescence on ICI-based therapies. Here, we review how cellular senescence and aging, either by directly altering the immune system fitness or indirectly through the modification of the tumor environment, may influence the cancer-immune response.

Keywords:  aging; cancer; immune checkpoint inhibitors; senescence; tumor

DOI:  https://doi.org/10.3390/cells10071568
Int J Mol Sci. 2021 Jun 08. pii: 6168. [Epub ahead of print]22(12):

MYC-Induced Replicative Stress: A Double-Edged Sword for Cancer Development and Treatment.

Laura Curti, Stefano Campaner.

  MYC is a transcription factor that controls the expression of a large fraction of cellular genes linked to cell cycle progression, metabolism and differentiation. MYC deregulation in tumors leads to its pervasive genome-wide binding of both promoters and distal regulatory regions, associated with selective transcriptional control of a large fraction of cellular genes. This pairs with alterations of cell cycle control which drive anticipated S-phase entry and reshape the DNA-replication landscape. Under these circumstances, the fine tuning of DNA replication and transcription becomes critical and may pose an intrinsic liability in MYC-overexpressing cancer cells. Here, we will review the current understanding of how MYC controls DNA and RNA synthesis, discuss evidence of replicative and transcriptional stress induced by MYC and summarize preclinical data supporting the therapeutic potential of triggering replicative stress in MYC-driven tumors.

Keywords:  DNA replication; MYC; cancer therapy; replicative stress; transcription; transcription stress

DOI:  https://doi.org/10.3390/ijms22126168
Korean J Physiol Pharmacol. 2021 Jul 01. 25(4): 297-305

Luteolin inhibits H2O2-induced cellular senescence via modulation of SIRT1 and p53.

Ri Zhe Zhu, Bing Si Li, Shang Shang Gao, Jae Ho Seo, Byung-Min Choi.

  Luteolin, a sort of flavonoid, has been reported to be involved in neuroprotective function via suppression of neuroinflammation. In this study, we investigated the protective effect of luteolin against oxidative stress-induced cellular senescence and its molecular mechanism using hydrogen peroxide (H2O2)-induced cellular senescence model in House Ear Institute-Organ of Corti 1 cells (HEI-OC1). Our results showed that luteolin attenuated senescent phenotypes including alterations of morphology, cell proliferation, senescence-associated β-galactosidase expression, DNA damage, as well as related molecules expression such as p53 and p21 in the oxidant challenged model. Interestingly, we found that luteolin induces expression of sirtuin 1 in dose- and time-dependent manners and it has protective role against H2O2-induced cellular senescence by upregulation of sirtuin 1 (SIRT1). In contrast, the inhibitory effect of luteolin on cellular senescence under oxidative stress was abolished by silencing of SIRT1. This study indicates that luteolin effectively protects against oxidative stress-induced cellular senescence through p53 and SIRT1. These results suggest that luteolin possesses therapeutic potentials against age-related hearing loss that are induced by oxidative stress.

Keywords:  Cellular senescence; Hydrogen peroxide; Luteolin; Sirtuin 1; Tumor suppressor protein p53

DOI:  https://doi.org/10.4196/kjpp.2021.25.4.297
J Med Chem. 2021 Jul 02.

Emerging Therapeutic Potential of SIRT6 Modulators.

Francesco Fiorentino, Antonello Mai, Dante Rotili.

Sirtuin 6 (SIRT6) is an NAD+-dependent protein deacylase and mono-ADP-ribosyltransferase of the sirtuin family with a wide substrate specificity. In vitro and in vivo studies have indicated that SIRT6 overexpression or activation has beneficial effects for cellular processes such as DNA repair, metabolic regulation, and aging. On the other hand, SIRT6 has contrasting roles in cancer, acting either as a tumor suppressor or promoter in a context-specific manner. Given its central role in cellular homeostasis, SIRT6 has emerged as a promising target for the development of small-molecule activators and inhibitors possessing a therapeutic potential in diseases ranging from cancer to age-related disorders. Moreover, specific modulators allow the molecular details of SIRT6 activity to be scrutinized and further validate the enzyme as a pharmacological target. In this Perspective, we summarize the current knowledge about SIRT6 pharmacology and medicinal chemistry and describe the features of the activators and inhibitors identified so far.

DOI: https://doi.org/10.1021/acs.jmedchem.1c00601