Autophagy-independent senescence and genome instability driven by targeted telomere dysfunction

Mar, Florie A; Debnath, Jayanta; Stohr, Bradley A.

doi:10.1080/15548627.2015.1017189

Cited by 17 publications

(6 citation statements)

References 67 publications

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“…5C). These findings are consistent with several recent studies demonstrating induction of autophagy during telomere dysfunction, oncogene-induced- and DNA damage-triggered senescence in fibroblasts as well as aged hematopoietic stem cells [52–57]. Cellular remodeling and reorganization of the endomembrane system occurs in senescent cells and activates autophagosome formation[54, 55].…”

Section: Discussionsupporting

confidence: 91%

Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell Fate

et al. 2018

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Aging severely limits myocardial repair and regeneration. Delineating the impact of age-associated factors such as short telomeres is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs). We hypothesized that short telomeres activate p53 and induce autophagy to elicit the age-associated change in CPC fate. We isolated CPCs and compared mouse strains with different telomere lengths for phenotypic characteristics of aging. Wild mouse strain Mus musculus castaneus (CAST) possessing short telomeres exhibits early cardiac aging with cardiac dysfunction, hypertrophy, fibrosis, and senescence, as compared with common lab strains FVB and C57 bearing longer telomeres. CAST CPCs with short telomeres demonstrate altered cell fate as characterized by cell cycle arrest, senescence, basal commitment, and loss of quiescence. Elongation of telomeres using a modified mRNA for telomerase restores youthful properties to CAST CPCs. Short telomeres induce autophagy in CPCs, a catabolic protein degradation process, as evidenced by reduced p62 and increased accumulation of autophagic puncta. Pharmacological inhibition of autophagosome formation reverses the cell fate to a more youthful phenotype. Mechanistically, cell fate changes induced by short telomeres are partially p53 dependent, as p53 inhibition rescues senescence and commitment observed in CAST CPCs, coincident with attenuation of autophagy. In conclusion, short telomeres activate p53 and autophagy to tip the equilibrium away from quiescence and proliferation toward differentiation and senescence, leading to exhaustion of CPCs. This study provides the mechanistic basis underlying age-associated cell fate changes that will enable identification of molecular strategies to prevent senescence of CPCs. Stem Cells 2018;36:868-880.

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Section: Discussionsupporting

confidence: 91%

Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell Fate

et al. 2018

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“…Autophagy and senescence tend to occur in parallel [15][16][17]; in a recent report, we demonstrated a linear relationship between autophagy and senescence induced by radiation in HCT-116 colorectal cancer cells [17]. A number of studies have investigated the putative, or potential, relationship between autophagy and senescence, generally concluding that, while autophagy may accelerate both oncogene-induced senescence and chemotherapy-induced senescence, senescence can and does occur even in the absence of autophagy [15,18,19]. However, one intrinsic limitation relating to studies of this relationship is that, when autophagy expresses its cytoprotective form, autophagy inhibition results in apoptotic cell death [20][21][22]; consequently, it becomes difficult to distinguish between the impact of autophagy inhibition on cell killing and the direct effects of autophagy inhibition on senescence.…”

Section: Introductionmentioning

confidence: 70%

Studies of Non-Protective Autophagy Provide Evidence that Recovery from Therapy-Induced Senescence is Independent of Early Autophagy

Saleh

Tyutyunyk‐Massey

Patel

et al. 2020

IJMS

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Autophagy and senescence, predominant responses that may dictate cell fate after chemotherapy or radiation, often occur in tandem. Cells in states of senescence and/or autophagy are frequently growth arrested. We have previously reported that tumor cells induced into senescence by therapy can re-emerge from the growth-arrested state, a phenomenon termed proliferative recovery. The current work shows that, while tumor cells collaterally induced into senescence and autophagy by etoposide, doxorubicin, or radiation undergo proliferative recovery, neither pharmacological nor genetic inhibition of early autophagy alter the extent of senescence or the ability of cells to recover from senescence. These findings confirm and extend our previous observations, essentially dissociating senescence from autophagy, and further indicate that re-emergence from senescence does not appear to be facilitated by or dependent on autophagy. Our results also provide additional evidence for the promotion of the non-protective form of autophagy by both chemotherapeutic drugs and radiation, which may complicate current efforts to inhibit autophagy for therapeutic benefit.

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“…The relationship between autophagy and senescence is still debatable. While the induction of senescence has been reported to be, at least in part, dependent on autophagy [31, 48], other studies concluded that senescence is independent of autophagy [65–66]. Despite the close correspondence between autophagy and senescence in parental and Ligase IV−/− HCT116 cells, pharmacological and genetic inhibition of autophagy did not seem to affect the promotion of senescence even at high doses of radiation, indicating that promotion of senescence is independent of autophagy in this experimental model.…”

Section: Discussionmentioning

confidence: 99%

Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Alotaibi¹,

Sharma²,

Saleh³

et al. 2016

Radiation Research

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Radiotherapy continues to be a primary modality in the treatment of cancer. DNA damage induced by radiation can promote apoptosis as well as both autophagy and senescence, where autophagy and senescence can theoretically function to prolong tumor survival. A primary aim of this work was to investigate the hypothesis that autophagy and/or senescence could be permissive for DNA repair, thereby facilitating tumor cell recovery from radiation-induced growth arrest and/or cell death. In addition, studies were designed to elucidate the involvement of autophagy and senescence in radiation sensitization by PARP inhibitors and the re-emergence of a proliferating tumor cell population. In the context of this work, the relationship between radiation-induced autophagy and senescence was also determined. Studies were performed using DNA repair proficient HCT116 colon carcinoma cells and a repair deficient Ligase IV (−/−) isogenic cell line. Irradiation promoted a parallel induction of autophagy and senescence that was strongly correlated with the extent of persistent H2AX phosphorylation in both cell lines; however inhibition of autophagy failed to suppress senescence, indicating that the two responses were dissociable. Irradiation resulted in a transient arrest in the HCT116 cells while arrest was prolonged in the Ligase IV (−/−) cells; however, both cell lines ultimately recovered proliferative function, which may reflect maintenance of DNA repair capacity. The PARP inhibitors (Olaparib) and (Niraparib) increased the extent of persistent DNA damage induced by radiation as well as the extent of both autophagy and senescence; neither cell line underwent significant apoptosis by radiation alone or in the presence of the PARP inhibitors. Inhibition of autophagy failed to attenuate radiation sensitization, indicating that autophagy was not involved in the action of the PARP inhibitors. As with radiation alone, despite sensitization by PARP inhibition, proliferative recovery was evident within a period of 10–20 days. While inhibition of DNA repair via PARP inhibition may initially sensitize tumor cells to radiation via the promotion of senescence, this strategy does not appear to interfere with proliferative recovery, which could ultimately contribute to disease recurrence.

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Autophagy-independent senescence and genome instability driven by targeted telomere dysfunction

Cited by 17 publications

References 67 publications

Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell Fate

Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell Fate

Studies of Non-Protective Autophagy Provide Evidence that Recovery from Therapy-Induced Senescence is Independent of Early Autophagy

Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

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