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  2. Selective Killing of RAS-Malignant Tissues by Exploiting Oncogene-Induced DNA Damage

Selective Killing of RAS-Malignant Tissues by Exploiting Oncogene-Induced DNA Damage

  • Cell Rep. 2019 Jul 2;28(1):119-131.e4. doi: 10.1016/j.celrep.2019.06.004.
Lada Murcia 1 Marta Clemente-Ruiz 1 Priscillia Pierre-Elies 2 Anne Royou 2 Marco Milán 3
Affiliations

Affiliations

  • 1 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10-12, 08028 Barcelona, Spain.
  • 2 Institut Européen de Chimie et Biologie, 2, rue Robert Escarpit, 33607 Pessac, France.
  • 3 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10-12, 08028 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain. Electronic address: marco.milan@irbbarcelona.org.
Abstract

Several oncogenes induce untimely entry into S phase and alter replication timing and progression, thereby generating replicative stress, a well-known source of genomic instability and a hallmark of Cancer. Using an epithelial model in Drosophila, we show that the Ras oncogene, which triggers G1/S transition, induces DNA damage and, at the same time, silences the DNA damage response pathway. Ras compromises ATR-mediated phosphorylation of the histone variant H2Av and ATR-mediated cell-cycle arrest in G2 and blocks, through ERK, Dp53-dependent induction of cell death. We found that ERK is also activated in normal tissues by an exogenous source of damage and that this activation is necessary to dampen the pro-apoptotic role of Dp53. We exploit the pro-survival role of ERK activation upon endogenous and exogenous sources of DNA damage to present evidence that its genetic or chemical inhibition can be used as a therapeutic opportunity to selectively eliminate RAS-malignant tissues.

Keywords

ATR; DNA damage; Dp53; ERK; cancer; cell death; genomic instability; malignancy; radiotherapy.

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