Specific Low/Endogenous Replication Stress Response Protects Genomic Stability via Controlled ROS Production in an Adaptive Way and Is Dysregulated in Transformed Cells
Cells are assaulted daily by stresses that jeopardize genome integrity. Primary human cells adapt their response to the intensity of replication stress (RS) in a diphasic manner: below a stress threshold, the canonical DNA damage response (cDDR) is not activated, but a noncanonical cellular response...
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2025-07-01
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| author | Bernard S. Lopez |
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| author_sort | Bernard S. Lopez |
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| description | Cells are assaulted daily by stresses that jeopardize genome integrity. Primary human cells adapt their response to the intensity of replication stress (RS) in a diphasic manner: below a stress threshold, the canonical DNA damage response (cDDR) is not activated, but a noncanonical cellular response, low-level stress-DDR (LoL-DDR), has recently been described. LoL-DDR prevents the accumulation of premutagenic oxidized bases (8-oxoguanine) through the production of ROS in an adaptive way. The production of RS-induced ROS (RIR) is tightly controlled: RIR are excluded from the nucleus and are produced by the NADPH oxidases <i>DUOX1/DUOX2</i>, which are controlled by NF-κB and PARP1; then, RIR activate the FOXO1-detoxifying pathway. Increasing the intensity of RS suppresses RIR via p53 and ATM. Notably, LoL-DDR is dysregulated in cancer cell lines, in which RIR are not produced by NADPH oxidases, are not detoxified under high-level stress, and favor the accumulation of 8-oxoguanine. LoL-DDR dysregulation occurred at an early stage of cancer progression in an in vitro model. Since, conversely, ROS trigger RS, this establishes a vicious cycle that continuously jeopardizes genome integrity, fueling tumorigenesis. These data reveal a novel type of ROS-controlled DNA damage response and demonstrate the fine-tuning of the cellular response to stress. The effects on genomic stability and carcinogenesis are discussed here. |
| format | Article |
| id | doaj-art-b9cb05204db64e6199936fd0125fbc7b |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-b9cb05204db64e6199936fd0125fbc7b2025-08-20T03:35:58ZengMDPI AGCells2073-44092025-07-011415118310.3390/cells14151183Specific Low/Endogenous Replication Stress Response Protects Genomic Stability via Controlled ROS Production in an Adaptive Way and Is Dysregulated in Transformed CellsBernard S. Lopez0Université Paris-Cité, INSERM U1016, UMR 8104 CNRS, Institut Cochin, 75014 Paris, FranceCells are assaulted daily by stresses that jeopardize genome integrity. Primary human cells adapt their response to the intensity of replication stress (RS) in a diphasic manner: below a stress threshold, the canonical DNA damage response (cDDR) is not activated, but a noncanonical cellular response, low-level stress-DDR (LoL-DDR), has recently been described. LoL-DDR prevents the accumulation of premutagenic oxidized bases (8-oxoguanine) through the production of ROS in an adaptive way. The production of RS-induced ROS (RIR) is tightly controlled: RIR are excluded from the nucleus and are produced by the NADPH oxidases <i>DUOX1/DUOX2</i>, which are controlled by NF-κB and PARP1; then, RIR activate the FOXO1-detoxifying pathway. Increasing the intensity of RS suppresses RIR via p53 and ATM. Notably, LoL-DDR is dysregulated in cancer cell lines, in which RIR are not produced by NADPH oxidases, are not detoxified under high-level stress, and favor the accumulation of 8-oxoguanine. LoL-DDR dysregulation occurred at an early stage of cancer progression in an in vitro model. Since, conversely, ROS trigger RS, this establishes a vicious cycle that continuously jeopardizes genome integrity, fueling tumorigenesis. These data reveal a novel type of ROS-controlled DNA damage response and demonstrate the fine-tuning of the cellular response to stress. The effects on genomic stability and carcinogenesis are discussed here.https://www.mdpi.com/2073-4409/14/15/1183DNA damage responseROSreplication stressgenetic instabilityNF-κBPARP1 |
| spellingShingle | Bernard S. Lopez Specific Low/Endogenous Replication Stress Response Protects Genomic Stability via Controlled ROS Production in an Adaptive Way and Is Dysregulated in Transformed Cells Cells DNA damage response ROS replication stress genetic instability NF-κB PARP1 |
| title | Specific Low/Endogenous Replication Stress Response Protects Genomic Stability via Controlled ROS Production in an Adaptive Way and Is Dysregulated in Transformed Cells |
| title_full | Specific Low/Endogenous Replication Stress Response Protects Genomic Stability via Controlled ROS Production in an Adaptive Way and Is Dysregulated in Transformed Cells |
| title_fullStr | Specific Low/Endogenous Replication Stress Response Protects Genomic Stability via Controlled ROS Production in an Adaptive Way and Is Dysregulated in Transformed Cells |
| title_full_unstemmed | Specific Low/Endogenous Replication Stress Response Protects Genomic Stability via Controlled ROS Production in an Adaptive Way and Is Dysregulated in Transformed Cells |
| title_short | Specific Low/Endogenous Replication Stress Response Protects Genomic Stability via Controlled ROS Production in an Adaptive Way and Is Dysregulated in Transformed Cells |
| title_sort | specific low endogenous replication stress response protects genomic stability via controlled ros production in an adaptive way and is dysregulated in transformed cells |
| topic | DNA damage response ROS replication stress genetic instability NF-κB PARP1 |
| url | https://www.mdpi.com/2073-4409/14/15/1183 |
| work_keys_str_mv | AT bernardslopez specificlowendogenousreplicationstressresponseprotectsgenomicstabilityviacontrolledrosproductioninanadaptivewayandisdysregulatedintransformedcells |