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Review
. 2018 Sep;246(1):12-40.
doi: 10.1002/path.5097. Epub 2018 Jul 19.

Integrating the DNA damage and protein stress responses during cancer development and treatment

Vassilis G Gorgoulis  1   2   3 , Dafni-Eleftheria Pefani  4 , Ioannis S Pateras  1 , Ioannis P Trougakos  5
Affiliations
Review

Integrating the DNA damage and protein stress responses during cancer development and treatment

Vassilis G Gorgoulis et al. J Pathol. 2018 Sep.

Abstract

During evolution, cells have developed a wide spectrum of stress response modules to ensure homeostasis. The genome and proteome damage response pathways constitute the pillars of this interwoven 'defensive' network. Consequently, the deregulation of these pathways correlates with ageing and various pathophysiological states, including cancer. In the present review, we highlight: (1) the structure of the genome and proteome damage response pathways; (2) their functional crosstalk; and (3) the conditions under which they predispose to cancer. Within this context, we emphasize the role of oncogene-induced DNA damage as a driving force that shapes the cellular landscape for the emergence of the various hallmarks of cancer. We also discuss potential means to exploit key cancer-related alterations of the genome and proteome damage response pathways in order to develop novel efficient therapeutic modalities. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Keywords: DNA damage response; cancer; homeostasis; oncogenes; proteome damage response; replication stress; stress response; tumor suppressors.

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Figures

Figure 1
Figure 1
Overview of homeostatic mechanisms. (A) DDRs and PDRs. (B) Hallmarks of stressors. (C) SRP components. See supplementary material for a detailed legend.
Figure 2
Figure 2
Synopsis of DNA damage type frequency and repair (A), DDR signalling cascades that activate the various checkpoints (B), and DNA repair mechanisms (C). See supplementary material for a detailed legend.
Figure 3
Figure 3
Repair routes for category‐S lesions (DDR surveillance). (A) Direct protein‐mediated reversal. (B) BER and NER. (C) TLS repair. See supplementary material for a detailed legend.
Figure 4
Figure 4
Repairing category‐D lesions (DDR surveillance). See supplementary material for a detailed legend.
Figure 5
Figure 5
A model depicting how oncogene‐induced RS aids the progressive formation of certain hallmarks of cancer (early events: steps 1–5), while paving the way for angiogenesis, evasion from immune surveillance, invasion, and metastasis (late events: step 6). See supplementary material for a detailed legend.
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