Cited by 881DNA Repair MechanismsCell death mechanisms and regulationCancer-related Molecular Pathways

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DNA damage-induced cell death: From specific DNA lesions to the DNA damage response and apoptosis

Roos, Wynand P., Kaina, Bernd·2013·Cancer Letters

DOI 10.1016/j.canlet.2012.01.007

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Abstract

DNA damaging agents are potent inducers of cell death triggered by apoptosis. Since these agents induce a plethora of different DNA lesions, it is firstly important to identify the specific lesions responsible for initiating apoptosis before the apoptotic executing pathways can be elucidated. Here, we describe specific DNA lesions that have been identified as apoptosis triggers, their repair and the signaling provoked by them. We discuss methylating agents such as temozolomide, ionizing radiation and cisplatin, all of them are important in cancer therapy. We show that the potentially lethal events for the cell are O(6)-methylguanine adducts that are converted by mismatch repair into DNA double-strand breaks (DSBs), non-repaired N-methylpurines and abasic sites as well as bulky adducts that block DNA replication leading to DSBs that are also directly induced following ionizing radiation. Transcriptional inhibition may also contribute to apoptosis. Cells are equipped with sensors that detect DNA damage and relay the signal via kinases to executors, who on their turn evoke a process that inhibits cell cycle progression and provokes DNA repair or, if this fails, activate the receptor and/or mitochondrial apoptotic cascade. The main DNA damage recognition factors MRN and the PI3 kinases ATM, ATR and DNA-PK, which phosphorylate a multitude of proteins and thus induce the DNA damage response (DDR), will be discussed as well as the downstream players p53, NF-κB, Akt and survivin. We review data and models describing the signaling from DNA damage to the apoptosis executing machinery and discuss the complex interplay between cell survival and death.

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Roos, W. P., Thomas, A. D., & Kaina, B. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2015.2 · Cited by 1,189
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See all 881

Authors: Roos, W. P., & Kaina, B.
Affiliations: Johannes Gutenberg University Mainz (DE)
Corresponding author: Kaina, Bernd
ORCID: Roos, Wynand P.
Kaina, Bernd
Venue: Cancer Letters
Publisher: Elsevier BV
Published: 2013-05
Volume: 332
Issue: 2
Pages: 237-248
ISSN: 0304-3835 (ISSN-L)
DOI: 10.1016/j.canlet.2012.01.007
OpenAlex: W2064488040
Cited by: 879
References: 187
Citations by year: 2026: 40 · 2025: 37 · 2024: 52 · 2023: 77 · 2022: 77 · 2021: 76 · 2020: 79 · 2019: 63 · 2018: 89 · 2017: 55 · 2016: 64 · 2015: 67 · 2014: 58 · 2013: 32
FWCI: 4.93
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Cancer Letters (publishedVersion)
PubMed (publishedVersion)
Funders: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: DNA damage response, apoptosis, DNA lesions, DNA mismatch repair, DNA double-strand breaks, abasic sites, bulky DNA adducts, ionizing radiation, temozolomide, cisplatin, DNA repair, MRN complex, ATM, ATR, DNA-dependent protein kinase, p53, NF-κB, Akt, survivin, transcriptional inhibition, cell cycle arrest, cancer therapy
MeSH terms: Survivin, Animals, Antineoplastic Agents, Cell Cycle, DNA, DNA Damage, DNA Repair, Guanine, Humans, Neoplasms, Phosphorylation, Radiation, Ionizing, Signal Transduction, NF-kappa B, Cell Death, Apoptosis, DNA Adducts, Inhibitor of Apoptosis Proteins, Proto-Oncogene Proteins c-akt

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DNA damage-induced cell death: From specific DNA lesions to the DNA damage response and apoptosis

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