Therapy-induced senescence (TIS) in Glioblastoma (GBM) residual disease and escape from TIS account for resistance and recurrence, but the mechanism of TIS manifestation remains obscure. Here, we demonstrate that replication stress (RS) is critical for the induction of TIS in residual cells by employing an in-vitro GBM therapy-resistance cellular model. Interestingly, we found a ‘bi-phasic’ mode of DNA damage after radiation treatment and revealed that the second phase of DNA damage arises majorly in the S-phase of residual cells due to RS. Mechanistically, we show that persistent phosphorylated ATR is a safeguard for radiation resilience, while the other canonical RS molecules remain unaltered during the second phase of DNA damage. Importantly, RS precedes the induction of senescence, and ATR inhibition results in TIS reduction, leading to apoptosis. Moreover, ATR inhibition sensitized PARP-1 inhibitor-induced enhanced TIS-mediated resistance, leading to cell death. Our study demonstrates the crucial role of RS in TIS induction and maintenance in GBM residual cells, and targeting ATR alone or in combination with a PARPi will be an effective strategy to eliminate TIS for better treatment outcomes.
Bi-phasic DNA damage and non-canonical replication stress response govern radiation-induced senescence in Glioblastoma
These authors contributed equally to the work
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Call for papers - Cilia and Flagella: from Basic Biology to Disease
We are welcoming submissions for our upcoming special issue: Cilia and Flagella: from Basic Biology to Disease. This issue will be coordinated by two Guest Editors: Pleasantine Mill (University of Edinburgh) and Lotte Pedersen (University of Copenhagen). Submission deadline: 1 March 2025.
Biologists @ 100 - join us in Liverpool in March 2025
We are excited to invite you to a unique scientific conference, celebrating the 100-year anniversary of The Company of Biologists, and bringing together our different communities. The conference will incorporate the Spring Meetings of the BSCB and the BSDB, the JEB Symposium Sensory Perception in a Changing World and a DMM programme on antimicrobial resistance. Find out more and register your interest to join us in March 2025 in Liverpool, UK.
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Mechanics play a fundamental role in cell physiology and represent physical mechanisms which cells use to influence function from the molecular to tissue scale. In this Review, Stefano Sala and colleagues clearly define mechanosensing and mechanotransduction, illustrate various mechanosensing mechanisms and discuss methods that cells use to regulate these processes.
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