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Rac1 GTPase-deficient HeLa cells present reduced DNA repair, proliferation, and survival under UV or gamma irradiation

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Abstract

Rac1 GTPase controls essential cellular functions related to the cytoskeleton, such as motility and adhesion. Rac1 is overexpressed in many tumor cells, including breast cancers, where it is also involved in the proliferation and checkpoint control necessary for the cell’s recovery after exposure to ionizing radiation. However, its role in DNA damage and repair remains obscure in other tumor cells and under different genotoxic conditions. Here, we compare HeLa cells with mutants exogenously expressing a dominant-negative Rac1 (HeLa-Rac1-N17) by their responses to DNA damage induced by gamma or UV radiation. In HeLa cells, these treatments led to increased levels of active Rac1 (Rac1-GTP) and of stress fibers, with a diminished ability to migrate compared to untreated cells. However, the reduction of Rac1-GTP in Rac1-N17-deficient clones resulted in much higher levels of polymerized stress fibers accompanied by a strong impairment of cell migration, even after both radiation treatments. With regard to proliferation and genomic stability, dominant-negative Rac1 cells were more sensitive to gamma and UV radiation, exhibiting reduced proliferation and survival consistent with increased DNA damage and delayed or reduced DNA repair observed in this Rac1-deficient clone. The DNA damage response, as indicated by pH2AX and pChk1 levels, was increased in HeLa cells but was not effectively triggered in the Rac1-N17 clone after radiation treatment, which is likely the main cause of DNA damage accumulation. These data suggest that Rac1 GTPase plays an important role in signaling and contributes to the sensitivity of cervical cancer cells under UV or gamma radiation treatments.

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Abbreviations

6-4PP:

Pyrimidine (6-4) pyrimidone photoproduct

8-oxoG:

8-Oxo-7,8-dihydroguanine

AML:

Acute myeloid leukemia

ATM:

Ataxia telangiectasia mutated kinase

ATR:

Ataxia telangiectasia mutated-related kinase

BSA:

Bovine serum albumin

CPD:

Cyclobutane pyrimidine dimmer

DAPI:

Dilactate 4′,6-di-amino-2-phenylindole

DDR:

DNA damage response

DME:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

DNA:

Deoxyribonucleic acid

DSB:

Double-strand break

DTT:

Dithiothreitol

EDTA:

Ethylenediaminetetraacetic acid

FBS:

Fetal bovine serum

FDR:

False-discovery rate algorithm

G2/M:

Gap 2/mitosis transition of cell cycle

GAP:

GTPase-activating proteins

GDP:

Guanosine diphosphate

GEF:

Guanine exchange factor

GO:

Gene ontology

GTP:

Guanosine triphosphate

Gy:

Gray

HR:

Homologous recombination

IPTG:

Isopropyl β-d thiogalactopyranoside

J/m2 :

Joule/meters2

MAPK:

Mitogen-activated protein kinase

MEF:

Mouse embryonic fibroblast

MLC:

Myosin light chain

NER:

Nucleotide excision repair

NHEJ:

Non-homologous end-joining

Nox:

NADPH–oxidase complex

PAGE:

Polyacrylamide gel electrophoresis

PAK:

p21-activating kinase

PBD-GST:

PAK1-binding domain linked to glutathione S-transferase

PBS:

Phosphate buffered saline

PIKK:

Phosphatidylinositol 3-kinase-related kinase protein

PMSF:

Phenylmethylsulfonyl fluoride

PPPI:

Physical protein–protein interaction

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SCGE:

Single-cell gel electrophoresis

SDS:

Sodium dodecyl sulfate

SSB:

Single-strand break

UV:

Ultraviolet radiation

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Acknowledgments

We thank Andressa P. Costa, Juliana R. Domingos, Benedita Oliveira, and Viviane Q. Machtura for technical assistance. We thank Drs. Margarida M. Hamada and Elizabeth Somessari and all of the staff of the CTRD-IPEN/CNEN, Sao Paulo-SP Brazil, for conducting the gamma irradiation of our samples. We also thank Prof. Dra. Marisa Gennari de Medeiros for allowing us to perform the Comet assays in her laboratory. Additionally, we thank the AJE staff and editors for their editing services, performed on the original version of the manuscript.

Conflict of interest

The authors declare that there are no conflicts of interest.

Funding

This research was supported by the Brazilian agency FAPESP through a Young Investigator Fellowship, #2008/58264-5, to FLF. JHO is recipient of a FAPESP PhD fellowship (142668/2009-5), GETS is the recipient of a CAPES Master Fellowship (2011/05822-3), and YTM is the recipient of a CNPq Scientific Initiation institutional fellowship.

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  1. Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, Av. Prof. Lineu Prestes, 748 - Bl.09i, Sl.922, Cidade Universitária, São Paulo, SP, CEP: 05508-900, Brazil

    Gisele Espinha, Juliana H. Osaki, Yuli T. Magalhaes & Fabio Luis Forti

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  1. Gisele Espinha
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Correspondence to Fabio Luis Forti.

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Espinha, G., Osaki, J.H., Magalhaes, Y.T. et al. Rac1 GTPase-deficient HeLa cells present reduced DNA repair, proliferation, and survival under UV or gamma irradiation. Mol Cell Biochem 404, 281–297 (2015). https://doi.org/10.1007/s11010-015-2388-0

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