Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress. / Larsen, Brian D; Benada, Jan; Yung, Philip Yuk Kwong; Bell, Ryan A V; Pappas, George; Urban, Vaclav; Ahlskog, Johanna K; Kuo, Tia T; Janscak, Pavel; Megeney, Lynn A; Elsässer, Simon J; Bartek, Jiri; Sørensen, Claus S.

In: Science, Vol. 376, No. 6592, 2022, p. 476-483.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Larsen, BD, Benada, J, Yung, PYK, Bell, RAV, Pappas, G, Urban, V, Ahlskog, JK, Kuo, TT, Janscak, P, Megeney, LA, Elsässer, SJ, Bartek, J & Sørensen, CS 2022, 'Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress', Science, vol. 376, no. 6592, pp. 476-483. https://doi.org/10.1126/science.abi6378

APA

Larsen, B. D., Benada, J., Yung, P. Y. K., Bell, R. A. V., Pappas, G., Urban, V., Ahlskog, J. K., Kuo, T. T., Janscak, P., Megeney, L. A., Elsässer, S. J., Bartek, J., & Sørensen, C. S. (2022). Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress. Science, 376(6592), 476-483. https://doi.org/10.1126/science.abi6378

Vancouver

Larsen BD, Benada J, Yung PYK, Bell RAV, Pappas G, Urban V et al. Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress. Science. 2022;376(6592):476-483. https://doi.org/10.1126/science.abi6378

Author

Larsen, Brian D ; Benada, Jan ; Yung, Philip Yuk Kwong ; Bell, Ryan A V ; Pappas, George ; Urban, Vaclav ; Ahlskog, Johanna K ; Kuo, Tia T ; Janscak, Pavel ; Megeney, Lynn A ; Elsässer, Simon J ; Bartek, Jiri ; Sørensen, Claus S. / Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress. In: Science. 2022 ; Vol. 376, No. 6592. pp. 476-483.

Bibtex

@article{645701bfce594882b66a2ca597b040bf,
title = "Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress",
abstract = "Genotoxic therapy such as radiation serves as a frontline cancer treatment, yet acquired resistance that leads to tumor reoccurrence is frequent. We found that cancer cells maintain viability during irradiation by reversibly increasing genome-wide DNA breaks, thereby limiting premature mitotic progression. We identify caspase-activated DNase (CAD) as the nuclease inflicting these de novo DNA lesions at defined loci, which are in proximity to chromatin-modifying CCCTC-binding factor (CTCF) sites. CAD nuclease activity is governed through phosphorylation by DNA damage response kinases, independent of caspase activity. In turn, loss of CAD activity impairs cell fate decisions, rendering cancer cells vulnerable to radiation-induced DNA double-strand breaks. Our observations highlight a cancer-selective survival adaptation, whereby tumor cells deploy regulated DNA breaks to delimit the detrimental effects of therapy-evoked DNA damage.",
keywords = "Chromatin, DNA/radiation effects, DNA Breaks, Double-Stranded, DNA Damage, DNA Repair, Neoplasms/genetics",
author = "Larsen, {Brian D} and Jan Benada and Yung, {Philip Yuk Kwong} and Bell, {Ryan A V} and George Pappas and Vaclav Urban and Ahlskog, {Johanna K} and Kuo, {Tia T} and Pavel Janscak and Megeney, {Lynn A} and Els{\"a}sser, {Simon J} and Jiri Bartek and S{\o}rensen, {Claus S}",
year = "2022",
doi = "10.1126/science.abi6378",
language = "English",
volume = "376",
pages = "476--483",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6592",

}

RIS

TY - JOUR

T1 - Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress

AU - Larsen, Brian D

AU - Benada, Jan

AU - Yung, Philip Yuk Kwong

AU - Bell, Ryan A V

AU - Pappas, George

AU - Urban, Vaclav

AU - Ahlskog, Johanna K

AU - Kuo, Tia T

AU - Janscak, Pavel

AU - Megeney, Lynn A

AU - Elsässer, Simon J

AU - Bartek, Jiri

AU - Sørensen, Claus S

PY - 2022

Y1 - 2022

N2 - Genotoxic therapy such as radiation serves as a frontline cancer treatment, yet acquired resistance that leads to tumor reoccurrence is frequent. We found that cancer cells maintain viability during irradiation by reversibly increasing genome-wide DNA breaks, thereby limiting premature mitotic progression. We identify caspase-activated DNase (CAD) as the nuclease inflicting these de novo DNA lesions at defined loci, which are in proximity to chromatin-modifying CCCTC-binding factor (CTCF) sites. CAD nuclease activity is governed through phosphorylation by DNA damage response kinases, independent of caspase activity. In turn, loss of CAD activity impairs cell fate decisions, rendering cancer cells vulnerable to radiation-induced DNA double-strand breaks. Our observations highlight a cancer-selective survival adaptation, whereby tumor cells deploy regulated DNA breaks to delimit the detrimental effects of therapy-evoked DNA damage.

AB - Genotoxic therapy such as radiation serves as a frontline cancer treatment, yet acquired resistance that leads to tumor reoccurrence is frequent. We found that cancer cells maintain viability during irradiation by reversibly increasing genome-wide DNA breaks, thereby limiting premature mitotic progression. We identify caspase-activated DNase (CAD) as the nuclease inflicting these de novo DNA lesions at defined loci, which are in proximity to chromatin-modifying CCCTC-binding factor (CTCF) sites. CAD nuclease activity is governed through phosphorylation by DNA damage response kinases, independent of caspase activity. In turn, loss of CAD activity impairs cell fate decisions, rendering cancer cells vulnerable to radiation-induced DNA double-strand breaks. Our observations highlight a cancer-selective survival adaptation, whereby tumor cells deploy regulated DNA breaks to delimit the detrimental effects of therapy-evoked DNA damage.

KW - Chromatin

KW - DNA/radiation effects

KW - DNA Breaks, Double-Stranded

KW - DNA Damage

KW - DNA Repair

KW - Neoplasms/genetics

U2 - 10.1126/science.abi6378

DO - 10.1126/science.abi6378

M3 - Journal article

C2 - 35482866

VL - 376

SP - 476

EP - 483

JO - Science

JF - Science

SN - 0036-8075

IS - 6592

ER -

ID: 305998791