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Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51
- Source :
- Cell death and differentiation 28 (2021): 2060–2082. doi:10.1038/s41418-020-00733-4, info:cnr-pdr/source/autori:Manic, Gwenola; Musella, Martina; Corradi, Francesca; Sistigu, Antonella; Vitale, Sara; Soliman Abdel Rehim, Sara; Mattiello, Luca; Malacaria, Eva; Galassi, Claudia; Signore, Michele; Pallocca, Matteo; Scalera, Stefano; Goeman, Frauke; De Nicola, Francesca; Guarracino, Andrea; Pennisi, Rosa; Antonangeli, Fabrizio; Sperati, Francesca; Baiocchi, Marta; Biffoni, Mauro; Fanciulli, Maurizio; Maugeri-Saccà, Marcello; Franchitto, Annapaola; Pichierri, Pietro; De Maria, Ruggero; Vitale, Ilio/titolo:Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51/doi:10.1038%2Fs41418-020-00733-4/rivista:Cell death and differentiation/anno:2021/pagina_da:2060/pagina_a:2082/intervallo_pagine:2060–2082/volume:28, Cell Death & Disease
- Publication Year :
- 2021
- Publisher :
- Edward Arnold, Oxford , Regno Unito, 2021.
-
Abstract
- Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations.
- Subjects :
- DNA Replication
Cell death
cancer stem cell
Colorectal cancer
replication stress
RAD51
Poly (ADP-Ribose) Polymerase-1
colorectal cancer stem cells
Mitosis
Antineoplastic Agents
Biology
PARP1
Downregulation and upregulation
Cancer stem cell
Settore MED/04 - PATOLOGIA GENERALE
Cell Line, Tumor
medicine
Humans
Molecular Biology
Mitotic catastrophe
MRE11 Homologue Protein
Cancer stem cells
Comment
Cell Biology
medicine.disease
Cancer research
Neoplastic Stem Cells
Rad51 Recombinase
Stem cell
Colorectal Neoplasms
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cell death and differentiation 28 (2021): 2060–2082. doi:10.1038/s41418-020-00733-4, info:cnr-pdr/source/autori:Manic, Gwenola; Musella, Martina; Corradi, Francesca; Sistigu, Antonella; Vitale, Sara; Soliman Abdel Rehim, Sara; Mattiello, Luca; Malacaria, Eva; Galassi, Claudia; Signore, Michele; Pallocca, Matteo; Scalera, Stefano; Goeman, Frauke; De Nicola, Francesca; Guarracino, Andrea; Pennisi, Rosa; Antonangeli, Fabrizio; Sperati, Francesca; Baiocchi, Marta; Biffoni, Mauro; Fanciulli, Maurizio; Maugeri-Saccà, Marcello; Franchitto, Annapaola; Pichierri, Pietro; De Maria, Ruggero; Vitale, Ilio/titolo:Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51/doi:10.1038%2Fs41418-020-00733-4/rivista:Cell death and differentiation/anno:2021/pagina_da:2060/pagina_a:2082/intervallo_pagine:2060–2082/volume:28, Cell Death & Disease
- Accession number :
- edsair.doi.dedup.....41194dadfbc654c63395e32f87fb93b7