DNA damage induces p53-independent apoptosis through ribosome stalling.

Autor: Boon NJ; Oncode Institute, Utrecht, Netherlands.; Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands., Oliveira RA; Oncode Institute, Utrecht, Netherlands.; Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands., Körner PR; Oncode Institute, Utrecht, Netherlands.; Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands., Kochavi A; Oncode Institute, Utrecht, Netherlands.; Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands., Mertens S; Oncode Institute, Utrecht, Netherlands.; Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands., Malka Y; Oncode Institute, Utrecht, Netherlands.; Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands., Voogd R; Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands., van der Horst SEM; Oncode Institute, Utrecht, Netherlands.; Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands., Huismans MA; Oncode Institute, Utrecht, Netherlands.; Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands., Smabers LP; Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands., Draper JM; Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands., Wessels LFA; Oncode Institute, Utrecht, Netherlands.; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands., Haahr P; Oncode Institute, Utrecht, Netherlands.; Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands.; Center for Gene Expression, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Roodhart JML; Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands., Schumacher TNM; Oncode Institute, Utrecht, Netherlands.; Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands., Snippert HJ; Oncode Institute, Utrecht, Netherlands.; Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands., Agami R; Oncode Institute, Utrecht, Netherlands.; Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands., Brummelkamp TR; Oncode Institute, Utrecht, Netherlands.; Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2024 May 17; Vol. 384 (6697), pp. 785-792. Date of Electronic Publication: 2024 May 16.
DOI: 10.1126/science.adh7950
Abstrakt: In response to excessive DNA damage, human cells can activate p53 to induce apoptosis. Cells lacking p53 can still undergo apoptosis upon DNA damage, yet the responsible pathways are unknown. We observed that p53-independent apoptosis in response to DNA damage coincided with translation inhibition, which was characterized by ribosome stalling on rare leucine-encoding UUA codons and globally curtailed translation initiation. A genetic screen identified the transfer RNAse SLFN11 and the kinase GCN2 as factors required for UUA stalling and global translation inhibition, respectively. Stalled ribosomes activated a ribotoxic stress signal conveyed by the ribosome sensor ZAKα to the apoptosis machinery. These results provide an explanation for the frequent inactivation of SLFN11 in chemotherapy-unresponsive tumors and highlight ribosome stalling as a signaling event affecting cell fate in response to DNA damage.
Databáze: MEDLINE
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