Oncotarget

Research Papers: Gerotarget (Focus on Aging):

The function of CUX1 in oxidative DNA damage repair is needed to prevent premature senescence of mouse embryo fibroblasts

Zubaidah M. Ramdzan _, Ranjana Pal, Simran Kaur, Lam Leduy, Ginette Bérubé, Sayeh Davoudi, Charles Vadnais and Alain Nepveu

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Oncotarget. 2015; 6:3613-3626. https://doi.org/10.18632/oncotarget.2919

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Abstract

Zubaidah M. Ramdzan1, Ranjana Pal1,5, Simran Kaur1,2, Lam Leduy1, Ginette Bérubé1, Sayeh Davoudi1,2, Charles Vadnais1,2, Alain Nepveu1,2,3,4

1Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada

2Department of Biochemistry, McGill University, Montreal, Quebec H3A 1A3, Canada

3Department of Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada

4Department of Oncology, McGill University, Montreal, Quebec H3A 1A3, Canada

5Department of Biological Sciences, Presidency University, Kolkata 700073, India

Correspondence to:

Alain Nepveu, e-mail: alain.nepveu@mcgill.ca

Keywords: cellular senescence, mouse embryo fibroblasts, oxidative DNA damage, 8-oxoguanine DNA glycosylase 1 (OGG1), CUX1

Received: November 17, 2014     Accepted: December 11, 2014     Published: January 08, 2015

ABSTRACT

Despite having long telomeres, mouse embryo fibroblasts (MEFs) senesce more rapidly than human diploid fibroblasts because of the accumulation of oxidative DNA damage. The CUX1 homeodomain protein was recently found to prevent senescence in RAS-driven cancer cells that produce elevated levels of reactive-oxygen species. Here we show that Cux1−/− MEFs are unable to proliferate in atmospheric (20%) oxygen although they can proliferate normally in physiological (3%) oxygen levels. CUX1 contains three domains called Cut repeats. Structure/function analysis established that a single Cut repeat domain can stimulate the DNA binding, Schiff-base formation, glycosylase and AP-lyase activities of 8-oxoguanine DNA glycosylase 1, OGG1. Strikingly and in contrast to previous reports, OGG1 exhibits efficient AP-lyase activity in the presence of a Cut repeat. Repair of oxidative DNA damage and proliferation in 20% oxygen were both rescued in Cux1−/− MEFs by ectopic expression of CUX1 or of a recombinant Cut repeat protein that stimulates OGG1 but is devoid of transcription activation potential. These findings reinforce the causal link between oxidative DNA damage and cellular senescence and suggest that the role of CUX1 as an accessory factor in DNA repair will be critical in physiological situations that generate higher levels of reactive oxygen species.


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