Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51.
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Colorectal Neoplasms
/ drug therapy
DNA Replication
/ drug effects
Humans
MRE11 Homologue Protein
/ drug effects
Mitosis
/ drug effects
Neoplastic Stem Cells
/ drug effects
Poly (ADP-Ribose) Polymerase-1
/ drug effects
Rad51 Recombinase
/ drug effects
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
30
07
2020
accepted:
30
12
2020
revised:
20
12
2020
pubmed:
4
2
2021
medline:
5
3
2022
entrez:
3
2
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33531658
doi: 10.1038/s41418-020-00733-4
pii: 10.1038/s41418-020-00733-4
pmc: PMC8257675
doi:
Substances chimiques
Antineoplastic Agents
0
MRE11 protein, human
0
PARP1 protein, human
EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
RAD51 protein, human
EC 2.7.7.-
Rad51 Recombinase
EC 2.7.7.-
MRE11 Homologue Protein
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2060-2082Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : Start-Up 2016 #18418
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : IG 2017 grant number 20417
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : RF_GR-2013-02357273
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : RF_RF-2016-02362022
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : Grant number RF_GR-2011-02351355
Commentaires et corrections
Type : CommentIn
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