Coordination between cell proliferation and apoptosis after DNA damage in Drosophila

Ruiz-Losada, Mireya; González, Raúl; Peropadre, Ana; Gil-Gálvez, Alejandro; Tena, Juan J.; Baonza, Antonio; Estella, Carlos

doi:10.1038/s41418-021-00898-6

Cited by 28 publications

(35 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multiple p53-dependent DDR genes, the majority in our study, were Xrp1-dependent, including the pro-apoptotic gene hid . Even though hid- reporters have been used as readouts of p53 activity (Fan et al 2010; Zhang et al 2014; Ruiz-Losada et al 2021; Chakravarti et al 2022), they may be more accurately described as targets of Xrp1. Other Xrp1 targets include DNA repair genes, GstD1, and Jun-kinase signaling.…”

Section: Discussionmentioning

confidence: 99%

The DNA Damage response and cell competition are p53- and Xrp1-dependent processes that suppress hyperplastic aneuploidy

Khan

Baker

2022

Preprint

View full text Add to dashboard Cite

It is important to understand how p53 suppresses tumorigenesis. P53 activity contributes to many instances of cell competition in mammals. This has not been seen for Drosophila p53, where the transcription factor Xrp1 is an effector of cell competition. Xrp1 is induced in a p53-dependent manner by DNA damage, and we report that Xrp1 mediates multiple functions of p53 in the DNA damage response, contributing to p53-dependent gene transcription and DNA damage-induced apoptosis. Differences in either Xrp1 or p53 activity, occurring between wild type and mutant cells experiencing mild genotoxic stress, both resulted in cell competition. Unexpectedly, cell competition due to differential p53 activity did not require Xrp1 but instead was restrained by Xrp1. We show that Xrp1 has a p53-independent role in removing genomically-altered cells. Both Xrp1 and p53 limit the accumulation of abnormal cells that results from genotoxicity, and we propose that genomic alterations enhance cellular growth of p53 mutant cells and promote cell competition, potentially contributing to the tumorigenesis in p53 mutants.

show abstract

Section: Discussionmentioning

confidence: 99%

The DNA Damage response and cell competition are p53- and Xrp1-dependent processes that suppress hyperplastic aneuploidy

Khan

Baker

2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The apoptotic function of E2f1 seems to be relevant only in p53 mutant cells, as robust apoptosis is observed in single E2f1 mutant discs at this time points (24 h post-IR) ( Wichmann et al, 2010 ). As E2f1 plays an important role regulating G1/S phase transition, and cell proliferation has been shown to influence both p53-dependent and -independent apoptosis, it is possible that the effect of E2f1 on IR-induced apoptosis could be an indirect effect due to altered cell proliferation ( Ruiz-Losada et al, 2022 ). The other E2f Drosophila member, E2f2, behaves as a repressor of IR-induced apoptosis during the p53-independent phase.…”

Section: Apoptotic Response To Irradiation-induced Dna Damage In ...mentioning

confidence: 99%

“…This apoptotic inhibition in non-proliferating cells is also observed in developmentally arrested cells. For example, post-mitotic cells of the Drosophila head or the ZNC in the wing imaginal disc are refractory to IR-induced apoptosis ( Moon et al, 2005 ; Kurtz et al, 2019 ; Ruiz-Losada et al, 2022 ). Similar response was described in Drosophila embryos, where the window of apoptotic sensitivity correlates with the timepoints when cells are highly proliferating ( Zhang et al, 2015 ).…”

Section: Differential Apoptotic Sensitivities To Dna Damage Depending...mentioning

confidence: 99%

Regulation and coordination of the different DNA damage responses in Drosophila

Baonza

Tur-Gracia

Pérez-Aguilera

et al. 2022

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

Cells have evolved mechanisms that allow them to respond to DNA damage to preserve genomic integrity and maintain tissue homeostasis. These responses include the activation of the cell cycle checkpoints and the repair mechanisms or the induction of apoptosis that eventually will eliminate damaged cells. These “life” vs. “death” decisions differ depending on the cell type, stages of development, and the proliferation status of the cell. The apoptotic response after DNA damage is of special interest as defects in its induction could contribute to tumorigenesis or the resistance of cancer cells to therapeutic agents such as radiotherapy. Multiples studies have elucidated the molecular mechanisms that mediate the activation of the DNA damage response pathway (DDR) and specifically the role of p53. However, much less is known about how the different cellular responses such as cell proliferation control and apoptosis are coordinated to maintain tissue homeostasis. Another interesting question is how the differential apoptotic response to DNA damage is regulated in distinct cell types. The use of Drosophila melanogaster as a model organism has been fundamental to understand the molecular and cellular mechanisms triggered by genotoxic stress. Here, we review the current knowledge regarding the cellular responses to ionizing radiation as the cause of DNA damage with special attention to apoptosis in Drosophila: how these responses are regulated and coordinated in different cellular contexts and in different tissues. The existence of intrinsic mechanisms that might attenuate the apoptotic pathway in response to this sort of DNA damage may well be informative for the differences in the clinical responsiveness of tumor cells after radiation therapy.

show abstract

“…We thus hypothesized that JAK/STAT interfered with the protective G2-stall of high JNK-signaling cells, and thereby increased apoptosis [31, 37], While Stat92E expression altered the proportion of S-phase cells in undamaged control discs, we observed no changes in the proportion of cells in G1 or G2 (Fig. S5E-H).…”

Section: Resultsmentioning

confidence: 95%

“…S1A) [31]. This model is supported by recent evidence that the universal integrator of molecular damage, p53, is activated by the G2/M kinase Cdk1 to induce apoptosis competence upon exit from G2 [37]. The G2 protective state is critical as high JNK/AP-1 signaling cells are shown to produce mitogens necessary to induce compensatory proliferation and regeneration [28, 38–40].…”

Section: Introductionmentioning

confidence: 92%

Mutual repression between JNK/AP-1 and JAK/STAT stratifies cell behaviors during tissue regeneration

Jaiswal

Engesser

Peyroton

et al. 2022

Preprint

View full text Add to dashboard Cite

Epithelial repair relies on the activation of stress signaling pathways to coordinate cellular repair behaviors. Their deregulation is implicated in chronic wound and cancer pathologies. Despite such translational importance, an understanding of how spatial patterns of signaling pathways and repair behaviors arise in damaged tissues remains elusive. Using TNF-α/Eiger- mediated inflammatory damage to Drosophila imaginal discs, we uncover that JNK/AP-1 signaling cells act as paracrine organizers and initiate a mutual repression network that spatially segregates JNK/AP-1 and JAK/STAT signaling cells into distinct populations. While JNK/AP-1 signaling cells produce JAK/STAT-activating Upd ligands, these signal-sending cells suppress activation of JAK/STAT via Ptp61F. Conversely, responding cells with activated JAK/STAT suppress JNK activation via Zfh2. The resulting bistable segregation of signaling domains is associated with distinct cellular tasks and regenerative potential. While JNK/AP-1 signaling cells at the wound center act as paracrine organizers, their cell cycle is senescently arrested. Thus, compensatory proliferation occurs exclusively in JAK/STAT signaling cells at the wound periphery. This spatial stratification is essential for proper tissue repair, as co-activation of JNK/AP-1 and JAK/STAT in the same cells creates conflicting inputs on cell cycle progression, leading to excess apoptosis of senescently arrested organizer cells. Finally, we demonstrate that bistable spatial segregation of JNK/AP-1 and JAK/STAT drives senescent and proliferative behaviors in transient as well as chronic tissue damage models, and importantly, in RasV12, scrib tumors under the influence of JNK/AP-1 activity. Revealing this previously uncharacterized regulatory network between JNK/AP-1, JAK/STAT and associated cell behaviors have important implications for our conceptual understanding of tissue repair, chronic wound pathologies and tumor microenvironments, where both pathways are strongly implicated.

show abstract

Coordination between cell proliferation and apoptosis after DNA damage in Drosophila

Cited by 28 publications

References 84 publications

The DNA Damage response and cell competition are p53- and Xrp1-dependent processes that suppress hyperplastic aneuploidy

The DNA Damage response and cell competition are p53- and Xrp1-dependent processes that suppress hyperplastic aneuploidy

Regulation and coordination of the different DNA damage responses in Drosophila

Mutual repression between JNK/AP-1 and JAK/STAT stratifies cell behaviors during tissue regeneration

Contact Info

Product

Resources

About