RAS Transformation Requires CUX1-Dependent Repair of Oxidative DNA Damage

Zubaidah M Ramdzan,Charles Vadnais,David Dankort,Marilène Paquet,Lu Yao,Laura Hulea,Guillaume Vandal,Lam Leduy,Alain Nepveu,Ranjana Pal,Sayeh Davoudi,Chantal Cadieux,Anthony N Karnezis

doi:10.1371/journal.pbio.1001807

Zubaidah M Ramdzan, Charles Vadnais + Show 11 more

Open Access

https://doi.org/10.1371/journal.pbio.1001807

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Abstract

Author SummaryIn the context of tumor development and progression, mutations are believed to accumulate owing to compromised DNA repair. Such mutations promote oncogenic growth. Yet cancer cells also need to sustain a certain level of DNA repair in order to replicate their DNA and successfully proliferate. Here we show that cancer cells that harbor an activated RAS oncogene exhibit heightened DNA repair capability, specifically in the base excision repair (BER) pathway that repairs oxidative DNA damage. RAS oncogenes alone do not transform primary cells but rather cause their senescence—that is, they stop dividing. As such, cellular senescence in this context is proposed to function as a tumor-suppressive mechanism. We show that CUX1, a protein that accelerates oxidative DNA damage repair, prevents cells from senescing and enables proliferation in the presence of a RAS oncogene. Consistent with this, RAS-induced senescence is also prevented by ectopic expression of OGG1, the DNA glycosylase that removes 8-oxoguanine, the most abundant oxidized base. Strikingly, CUX1 expression in transgenic mice enables the emergence of tumors with spontaneous activating Kras mutations. Conversely, knockdown of CUX1 is synthetic lethal for RAS-transformed cells, thereby revealing a potential Achilles' heel of these cancer cells. Overall, the work provides insight into understanding the role of DNA repair in cancer progression, showing that while DNA damage-induced mutations promote tumorigenesis, sustained RAS-dependent tumorigenesis requires suppression of DNA damage. The heightened dependency of RAS-transformed cells on base excision repair may provide a therapeutic window that could be exploited with drugs that specifically target this pathway.

Highlights

Oncogenic potential of RAS signaling is frequently activated in human cancers as a result of point mutations in RAS genes or alterations in upstream or downstream signaling proteins
The concomitant accumulation of p53, p21CDKN1A, and p16INK4a, together with the finding that proliferation arrest could be bypassed by inactivating the Rb and p53 pathways, promoted the concept that oncogeneinduced senescence was a component of the DNA damage response (DDR) that evolved as a tumor suppression mechanism [5]
We show that cancer cells that harbor an activated RAS oncogene exhibit heightened DNA repair capability, in the base excision repair (BER) pathway that repairs oxidative DNA damage

Summary

Introduction

Oncogenic potential of RAS signaling is frequently activated in human cancers as a result of point mutations in RAS genes or alterations in upstream or downstream signaling proteins (reviewed in [1,2]). Oncogenic RAS cannot, transform primary culture cells alone but requires cooperation with other oncogenic stimulants, a finding that contributed to the concept of multistep tumorigenesis [3]. Subsequent studies have revealed that oncogenic RAS, as well as other oncogenes, cause senescence in both rodent and human primary cells [4]. RAS-induced senescence results from the heightened production of reactive oxygen species (ROS) [6,7] through increased expression and activity of NADPH oxidases [8,9]. Among the most deleterious of ROS-induced DNA adducts is 7,8-dihydro-8oxoguanine (8-oxoG), which can mispair with adenine to cause GC to T-A transversion mutations [10].

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