DNA damage induces p53-independent apoptosis through ribosome stalling

Nicolaas J Boon; Rafaela A Oliveira; Pierré-René Körner; Adva Kochavi; Sander Mertens; Yuval Malka; Rhianne Voogd; Suzanne E M van der Horst; Maarten A Huismans; Lidwien P Smabers; Jonne M Draper; Lodewyk F A Wessels; Peter Haahr; Jeanine M L Roodhart; Ton N M Schumacher; Hugo J Snippert; Reuven Agami; Thijn R Brummelkamp

doi:10.1126/science.adh7950

DNA damage induces p53-independent apoptosis through ribosome stalling

Nicolaas J Boon, Rafaela A Oliveira, Pierré-René Körner, Adva Kochavi, Sander Mertens, Yuval Malka, Rhianne Voogd, Suzanne E M van der Horst, Maarten A Huismans, Lidwien P Smabers, Jonne M Draper, Lodewyk F A Wessels, Peter Haahr, Jeanine M L Roodhart, Ton N M Schumacher, Hugo J Snippert, Reuven Agami^*, Thijn R Brummelkamp^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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 ZAKa 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.

Original language	English
Pages (from-to)	785-792
Number of pages	8
Journal	Science
Volume	384
Issue number	6697
DOIs	https://doi.org/10.1126/science.adh7950
Publication status	Published - 17 May 2024

Keywords

Apoptosis
Apoptosis Regulatory Proteins
DNA Damage
Humans
Leucine/pharmacology
Protein Biosynthesis
Protein Serine-Threonine Kinases/metabolism
Repressor Proteins
Ribosomes/metabolism
Signal Transduction
Tumor Suppressor Protein p53/metabolism

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Boon, N. J., Oliveira, R. A., Körner, P.-R., Kochavi, A., Mertens, S., Malka, Y., Voogd, R., van der Horst, S. E. M., Huismans, M. A., Smabers, L. P., Draper, J. M., Wessels, L. F. A., Haahr, P., Roodhart, J. M. L., Schumacher, T. N. M., Snippert, H. J., Agami, R., & Brummelkamp, T. R. (2024). DNA damage induces p53-independent apoptosis through ribosome stalling. Science, 384(6697), 785-792. https://doi.org/10.1126/science.adh7950

@article{25e1fcff59324d71b97dc327bb37573b,

title = "DNA damage induces p53-independent apoptosis through ribosome stalling",

abstract = "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 ZAKa 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.",

keywords = "Apoptosis, Apoptosis Regulatory Proteins, DNA Damage, Humans, Leucine/pharmacology, Protein Biosynthesis, Protein Serine-Threonine Kinases/metabolism, Repressor Proteins, Ribosomes/metabolism, Signal Transduction, Tumor Suppressor Protein p53/metabolism",

author = "Boon, {Nicolaas J} and Oliveira, {Rafaela A} and Pierr{\'e}-Ren{\'e} K{\"o}rner and Adva Kochavi and Sander Mertens and Yuval Malka and Rhianne Voogd and {van der Horst}, {Suzanne E M} and Huismans, {Maarten A} and Smabers, {Lidwien P} and Draper, {Jonne M} and Wessels, {Lodewyk F A} and Peter Haahr and Roodhart, {Jeanine M L} and Schumacher, {Ton N M} and Snippert, {Hugo J} and Reuven Agami and Brummelkamp, {Thijn R}",

year = "2024",

month = may,

day = "17",

doi = "10.1126/science.adh7950",

language = "English",

volume = "384",

pages = "785--792",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6697",

}

Boon, NJ, Oliveira, RA, Körner, P-R, Kochavi, A, Mertens, S, Malka, Y, Voogd, R, van der Horst, SEM, Huismans, MA, Smabers, LP, Draper, JM, Wessels, LFA, Haahr, P, Roodhart, JML, Schumacher, TNM, Snippert, HJ, Agami, R & Brummelkamp, TR 2024, 'DNA damage induces p53-independent apoptosis through ribosome stalling', Science, vol. 384, no. 6697, pp. 785-792. https://doi.org/10.1126/science.adh7950

TY - JOUR

T1 - DNA damage induces p53-independent apoptosis through ribosome stalling

AU - Boon, Nicolaas J

AU - Oliveira, Rafaela A

AU - Körner, Pierré-René

AU - Kochavi, Adva

AU - Mertens, Sander

AU - Malka, Yuval

AU - Voogd, Rhianne

AU - van der Horst, Suzanne E M

AU - Huismans, Maarten A

AU - Smabers, Lidwien P

AU - Draper, Jonne M

AU - Wessels, Lodewyk F A

AU - Haahr, Peter

AU - Roodhart, Jeanine M L

AU - Schumacher, Ton N M

AU - Snippert, Hugo J

AU - Agami, Reuven

AU - Brummelkamp, Thijn R

PY - 2024/5/17

Y1 - 2024/5/17

N2 - 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 ZAKa 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.

AB - 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 ZAKa 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.

KW - Apoptosis

KW - Apoptosis Regulatory Proteins

KW - DNA Damage

KW - Humans

KW - Leucine/pharmacology

KW - Protein Biosynthesis

KW - Protein Serine-Threonine Kinases/metabolism

KW - Repressor Proteins

KW - Ribosomes/metabolism

KW - Signal Transduction

KW - Tumor Suppressor Protein p53/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85193507786&partnerID=8YFLogxK

U2 - 10.1126/science.adh7950

DO - 10.1126/science.adh7950

M3 - Article

C2 - 38753784

SN - 0036-8075

VL - 384

SP - 785

EP - 792

JO - Science

JF - Science

IS - 6697

ER -

DNA damage induces p53-independent apoptosis through ribosome stalling

Abstract

Keywords

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