Cytoplasmic chromatin fragments—from mechanisms to therapeutic potential

Senescent cells, damaged cells that permanently exit the cell cycle, play important roles in development, tissue homeostasis, and tumorigenesis. Although many of these roles are beneficial in acute responses to stress and damage, the persistent accumulation of senescent cells is associated with many chronic diseases through their proinflammatory senescence-associated secretory phenotype (SASP). SASP expression is linked to DNA damage; however, the mechanisms that control the SASP are incompletely understood. More recently, it has been shown that senescent cells shed fragments of nuclear chromatin into the cytoplasm, so called cytoplasmic chromatin fragments (CCF). Here, we provide an overview of the current evidence linking DNA damage to the SASP through the formation of CCF. We describe mechanisms of CCF generation and their functional role in senescent cells, with emphasis on therapeutic potential.

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The NUCKS1-SKP2-p21/p27 axis controls S phase entry

10.1101/2021.06.29.450420 ◽

2021 ◽

Author(s):

Samuel Hume ◽

Claudia P Grou ◽

Pauline Lascaux ◽

Vincenzo D'Angiolella ◽

Arnaud J Legrand ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Ubiquitin Ligase ◽

Transcriptional Repression ◽

S Phase ◽

Tissue Homeostasis ◽

Cycle Arrest ◽

Checkpoint Pathway ◽

Dna Damage Signalling ◽

Phase Entry

Efficient entry into S phase of the cell cycle is necessary for embryonic development and tissue homeostasis. However, unscheduled S phase entry triggers DNA damage and promotes oncogenesis, underlining the requirement for strict control. Here, we identify the NUCKS1-SKP2-p21/p27 axis as a checkpoint pathway for the G1/S transition. In response to mitogenic stimulation, NUCKS1, a transcription factor, is recruited to chromatin to activate expression of SKP2, the F-box component of the SCFSKP2 ubiquitin ligase, leading to degradation of p21 and p27 and promoting progression into S phase. In contrast, DNA damage induces p53-dependent transcriptional repression of NUCKS1, leading to SKP2 downregulation, p21/p27 upregulation, and cell cycle arrest. We propose that the NUCKS1-SKP2-p21/p27 axis integrates mitogenic and DNA damage signalling to control S phase entry. TCGA data reveal that this mechanism is hijacked in cancer, potentially allowing cancer cells to sustain uncontrolled proliferation.

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Cellular Senescence: Mechanisms and Therapeutic Potential

Biomedicines ◽

10.3390/biomedicines9121769 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1769

Author(s):

Zehuan Liao ◽

Han Lin Yeo ◽

Siaw Wen Wong ◽

Yan Zhao

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cellular Senescence ◽

Biological Process ◽

Therapeutic Potential ◽

Biological Processes ◽

Limb Patterning ◽

Cycle Arrest ◽

Major Interest ◽

Secretory Phenotype

Cellular senescence is a complex and multistep biological process which cells can undergo in response to different stresses. Referring to a highly stable cell cycle arrest, cellular senescence can influence a multitude of biological processes—both physiologically and pathologically. While phenotypically diverse, characteristics of senescence include the expression of the senescence-associated secretory phenotype, cell cycle arrest factors, senescence-associated β-galactosidase, morphogenesis, and chromatin remodelling. Persistent senescence is associated with pathologies such as aging, while transient senescence is associated with beneficial programmes, such as limb patterning. With these implications, senescence-based translational studies, namely senotherapy and pro-senescence therapy, are well underway to find the cure to complicated diseases such as cancer and atherosclerosis. Being a subject of major interest only in the recent decades, much remains to be studied, such as regarding the identification of unique biomarkers of senescent cells. This review attempts to provide a comprehensive understanding of the diverse literature on senescence, and discuss the knowledge we have on senescence thus far.

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The Distinct Function of p21Waf1/Cip1 With p16Ink4a in Modulating Aging Phenotypes of Werner Syndrome by Affecting Tissue Homeostasis

Frontiers in Genetics ◽

10.3389/fgene.2021.597566 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yongjin Zhang ◽

Chihao Shao ◽

Haili Li ◽

Kun Wu ◽

Lixin Gong ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Stem Cell ◽

Cellular Senescence ◽

Cellular Proliferation ◽

Werner Syndrome ◽

Survival Curve ◽

Cell Cycle Control ◽

Tissue Homeostasis ◽

Premature Aging

Human Werner syndrome (WS) is an autosomal recessive progeria disease. A mouse model of WS manifests the disease through telomere dysfunction-induced aging phenotypes, which might result from cell cycle control and cellular senescence. Both p21Waf1/Cip1 (p21, encoded by the Cdkn1a gene) and p16Ink4a (p16, encoded by the Ink4a gene) are cell cycle inhibitors and are involved in regulating two key pathways of cellular senescence. To test the effect of p21 and p16 deficiencies in WS, we crossed WS mice (DKO) with p21–/– or p16–/– mice to construct triple knockout (p21-TKO or p16-TKO) mice. By studying the survival curve, bone density, regenerative tissue (testis), and stem cell capacity (intestine), we surprisingly found that p21-TKO mice displayed accelerated premature aging compared with DKO mice, while p16-TKO mice showed attenuation of the aging phenotypes. The incidence of apoptosis and cellular senescence were upregulated in p21-TKO mice tissue and downregulated in p16-TKO mice. Surprisingly, cellular proliferation in p21-TKO mice tissue was also upregulated, and the p21-TKO mice did not show telomere shortening compared with age-matched DKO mice, although p16-TKO mice displayed obvious enhancement of telomere lengthening. Consistent with these phenotypes, the SIRT1-PGC1 pathway was upregulated in p16-TKO but downregulated in p21-TKO compared with DKO mouse embryo fibroblasts (MEFs). However, the DNA damage response pathway was highly activated in p21-TKO, but rescued in p16-TKO, compared with DKO MEFs. These data suggest that p21 protected the stem cell reservoir by regulating cellular proliferation and turnover at a proper rate and that p21 loss in WS activated fairly severe DNA damage responses (DDR), which might cause an abnormal increase in tissue homeostasis. On the other hand, p16 promoted cellular senescence by inhibiting cellular proliferation, and p16 deficiency released this barrier signal without causing severe DDR.

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Targeting LDHC dysregulates the cell cycle and improves sensitivity to cisplatin and olaparib

10.1101/2021.03.03.433525 ◽

2021 ◽

Author(s):

Adviti Naik ◽

Julie Decock

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Dna Damage ◽

Cancer Cell ◽

Therapeutic Potential ◽

Cell Cycle Checkpoint ◽

Metabolic Reprogramming ◽

Mitotic Catastrophe ◽

Breast Cancer Cell Lines ◽

Term Survival

The cancer testis antigen (CTA) lactate dehydrogenase C (LDHC) is a promising anti-cancer target with tumor-specific expression, immunogenicity and a role in metabolic reprogramming. Interrogation of the TCGA breast cancer cohort demonstrates upregulation of LDHC expression, conferring unfavorable prognosis. Although the role of LDHC is well characterized in spermatocytes, its role in tumors remains largely unknown. We investigated whether LDHC, in analogy with other CTAs, is involved in regulating genomic stability and may be targeted to affect tumor cellular fitness. Silencing LDHC in four breast cancer cell lines significantly increased the presence of giant cells and nuclear aberrations, DNA damage and apoptosis. Further analysis of LDHC silenced cells demonstrated aberrant cell cycle progression with differential expression of cell cycle checkpoint and DNA damage response regulators, resulting in a shortened G1 phase, intra-S checkpoint override and G2/M checkpoint adaptation. In addition, LDHC silencing induced microtubule destabilization, culminating in increased mitotic catastrophe and reduced long-term survival. Notably, cisplatin and olaparib treatment further reduced survival of LDHC silenced cells. In conclusion, this study supports the therapeutic potential of targeting LDHC to mitigate cancer cell survival, and to improve sensitivity to DNA damaging and DNA damage repair inhibiting agents.

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Uncoupling the Senescence-Associated Secretory Phenotype from Cell Cycle Exit via Interleukin-1 Inactivation Unveils Its Protumorigenic Role

Molecular and Cellular Biology ◽

10.1128/mcb.00586-18 ◽

2019 ◽

Vol 39 (12) ◽

Cited By ~ 13

Author(s):

Lena Lau ◽

Angelo Porciuncula ◽

Alex Yu ◽

Yoichiro Iwakura ◽

Gregory David

Keyword(s):

Cell Cycle ◽

Immune Cell ◽

Therapeutic Potential ◽

Interleukin 1 ◽

Transcriptome Profiling ◽

Cell Cycle Exit ◽

Cycle Arrest ◽

Suppressor Mechanism ◽

Secretory Phenotype

ABSTRACT Cellular senescence has emerged as a potent tumor suppressor mechanism in numerous human neoplasias. Senescent cells secrete a distinct set of factors, collectively termed the senescence-associated secretory phenotype (SASP), which has been postulated to carry both pro- and antitumorigenic properties depending on tissue context. However, the in vivo effect of the SASP is poorly understood due to the difficulty of studying the SASP independently of other senescence-associated phenotypes. Here, we report that disruption of the interleukin-1 (IL-1) pathway completely uncouples the SASP from other senescence-associated phenotypes such as cell cycle exit. Transcriptome profiling of IL-1 receptor (IL-1R)-depleted senescent cells indicates that IL-1 controls the late arm of the senescence secretome, which consists of proinflammatory cytokines induced by NF-κB. Our data suggest that both IL-1α and IL-1β signal through IL-1R to upregulate the SASP in a cooperative manner. Finally, we show that IL-1α inactivation impairs tumor progression and immune cell infiltration without affecting cell cycle arrest in a mouse model of pancreatic cancer, highlighting the protumorigenic property of the IL-1-dependent SASP in this context. These findings provide novel insight into the therapeutic potential of targeting the IL-1 pathway in inflammatory cancers.

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Senescence-Associated Secretory Phenotype as a Hinge Between Cardiovascular Diseases and Cancer

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.763930 ◽

2021 ◽

Vol 8 ◽

Author(s):

Priyanka Banerjee ◽

Sivareddy Kotla ◽

Loka Reddy Velatooru ◽

Rei J. Abe ◽

Elizabeth A. Davis ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cardiovascular Diseases ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Replicative Senescence ◽

Cancer Treatments ◽

Cycle Arrest ◽

Secretory Phenotype ◽

Mediate Cell

Overlapping risks for cancer and cardiovascular diseases (CVD), the two leading causes of mortality worldwide, suggest a shared biology between these diseases. The role of senescence in the development of cancer and CVD has been established. However, its role as the intersection between these diseases remains unclear. Senescence was originally characterized by an irreversible cell cycle arrest after a high number of divisions, namely replicative senescence (RS). However, it is becoming clear that senescence can also be instigated by cellular stress, so-called stress-induced premature senescence (SIPS). Telomere shortening is a hallmark of RS. The contribution of telomere DNA damage and subsequent DNA damage response/repair to SIPS has also been suggested. Although cellular senescence can mediate cell cycle arrest, senescent cells can also remain metabolically active and secrete cytokines, chemokines, growth factors, and reactive oxygen species (ROS), so-called senescence-associated secretory phenotype (SASP). The involvement of SASP in both cancer and CVD has been established. In patients with cancer or CVD, SASP is induced by various stressors including cancer treatments, pro-inflammatory cytokines, and ROS. Therefore, SASP can be the intersection between cancer and CVD. Importantly, the conventional concept of senescence as the mediator of cell cycle arrest has been challenged, as it was recently reported that chemotherapy-induced senescence can reprogram senescent cancer cells to acquire “stemness” (SAS: senescence-associated stemness). SAS allows senescent cancer cells to escape cell cycle arrest with strongly enhanced clonogenic growth capacity. SAS supports senescent cells to promote both cancer and CVD, particularly in highly stressful conditions such as cancer treatments, myocardial infarction, and heart failure. As therapeutic advances have increased overlapping risk factors for cancer and CVD, to further understand their interaction may provide better prevention, earlier detection, and safer treatment. Thus, it is critical to study the mechanisms by which these senescence pathways (SAS/SASP) are induced and regulated in both cancer and CVD.

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Loss of p16: A Bouncer of the Immunological Surveillance?

Life ◽

10.3390/life11040309 ◽

2021 ◽

Vol 11 (4) ◽

pp. 309

Author(s):

Kelly E. Leon ◽

Naveen Kumar Tangudu ◽

Katherine M. Aird ◽

Raquel Buj

Keyword(s):

Cell Cycle ◽

Transcriptional Regulation ◽

Tumor Immunity ◽

Human Cancer ◽

Tumor Suppressor Protein ◽

Current Evidence ◽

Immunological Surveillance ◽

A Cell ◽

Secretory Phenotype ◽

Correlative Studies

p16INK4A (hereafter called p16) is an important tumor suppressor protein frequently suppressed in human cancer and highly upregulated in many types of senescence. Although its role as a cell cycle regulator is very well delineated, little is known about its other non-cell cycle-related roles. Importantly, recent correlative studies suggest that p16 may be a regulator of tissue immunological surveillance through the transcriptional regulation of different chemokines, interleukins and other factors secreted as part of the senescence-associated secretory phenotype (SASP). Here, we summarize the current evidence supporting the hypothesis that p16 is a regulator of tumor immunity.

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