Cell cycle inhibitor, p19INK4d, promotes cell survival and decreases chromosomal aberrations after genotoxic insult due to enhanced DNA repair.
Genome integrity and cell proliferation and survival are regulated by an intricate network of pathways that includes cell cycle checkpoints, DNA repair and recombination, and programmed cell death. It makes sense that there should be a coordinated regulation of these different processes, but the components of such mechanisms remain unknown. In this report, we demonstrate that p19INK4d expression enhances cell survival under genotoxic conditions. By using p19INK4d-overexpressing clones, we demonstrated that p19INK4d expression correlates with the cellular resistance to UV treatment with increased DNA repair activity against UV-induced lesions. On the contrary, cells transfected with p19INK4d antisense cDNA show reduced ability to repair DNA damage and increased sensitivity to genotoxic insult when compared with their p19INK4d-overexpressing counterparts. Consistent with these findings, our studies also show that p19INK4d-overexpressing cells present not only a minor accumulation of UV-induced chromosomal aberrations but a lower frequency of spontaneous chromosome abnormalities than p19INK4d-antisense cells. Lastly, we suggest that p19INK4d effects are dissociated from its role as CDK4/6 inhibitor. The results presented herein support a crucial role for p19INK4d in regulating genomic stability and overall cell viability under conditions of genotoxic stress. We propose that p19INK4d would belong to a protein network that would integrate DNA repair, apoptotic and checkpoint mechanisms in order to maintain the genomic integrity.
Scassa
María E
ME
Laboratorio de Biología Molecular, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria Pabellón II, 1428 Buenos Aires, Argentina.
Marazita
Mariela C
MC
Ceruti
Julieta M
JM
Carcagno
Abel L
AL
Sirkin
Pablo F
PF
González-Cid
Marcela
M
Pignataro
Omar P
OP
Cánepa
Eduardo T
ET
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology* / Q000528:radiation effects; D002869:Chromosome Aberrations; D003114:Colony-Forming Units Assay; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000378:metabolism* / Q000494:pharmacology*; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair / Q000502:physiology* / Q000528:radiation effects; D042822:Genomic Instability; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D011740:Pyrimidine Dimers; D012333:RNA, Messenger / Q000235:genetics; D011836:Radiation Tolerance; D013936:Thymidine / Q000378:metabolism; D014466:Ultraviolet Rays
C493974:CDKN2D protein, human; C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; D011740:Pyrimidine Dimers; D012333:RNA, Messenger; D013936:Thymidine