Nune Darbinian-Sarkissian

Publications of Nune Darbinian-Sarkissian

• Evidence for the involvement of Puralpha in response to DNA replication stress.

  Authors: Huichen Wang, Meijuan Wang, Krzysztof Reiss, Nune Darbinian-Sarkissian, Edward M Johnson, George Iliakis, Shohreh Amini, Kamel Khalili, Jay Rappaport

  Cancer biology & therapy. 05/2007; 6(4):596-602.

  Puralpha is a sequence-specific nucleic acid binding protein that is involved in multiple cellular functions including regulation of transcription, initiation of DNA replication, cell cyclePuralpha is a sequence-specific nucleic acid binding protein that is involved in multiple cellular functions including regulation of transcription, initiation of DNA replication, cell cycle progression, and neuronal cell differentiation. Its potential role in DNA repair has not been explored. We have now analyzed the role of Puralpha in the cellular response to replication-associated DNA repair of double-strand breaks (DSBs) using Puralpha knockout mouse embryo fibroblasts (MEFs). We found that Puralpha negative cells are hypersensitive to the DNA replication inhibitor, hydroxyurea (HU), and that HU induces excessive DSBs, which delayed the resumption of cell cycle progression after HU treatment. Reintroduction of Pura into Pura null cells reduced the accumulation of DSBs and enhanced DNA end joining. These results suggest a role for Puralpha as a caretaker protein that is involved in the repair of DSBs induced by stalled replication forks.

• Dysregulation of NGF-signaling and Egr-1 expression by Tat in neuronal cell culture.

  Authors: Nune Darbinian-Sarkissian, Marta Czernik, Francesca Peruzzi, Jennifer Gordon, Jay Rappaport, Krzysztof Reiss, Kamel Khalili, Shohreh Amini

  Journal of cellular physiology. 10/2006; 208(3):506-15.

  Examination of signal transduction pathways that modulate neuronal cell differentiation and protection against apoptosis has revealed a central role for the MAPK/Erk cascade. The activation ofExamination of signal transduction pathways that modulate neuronal cell differentiation and protection against apoptosis has revealed a central role for the MAPK/Erk cascade. The activation of MAPK/Erk through the TrkA NGF signaling pathway is critical for growth and survival of neuronal cells. Here, we investigate the impact of HIV-1 Tat on the NGF-signaling pathway in SK-N-MC neuroblastoma cells. Expression of Tat decreased cell growth and induced apoptosis. Our results revealed dysregulation of various steps involved in the NGF pathway including suppression of MAPK, and inhibition of the promoter activity of Egr-1, a key pleiotropic mediator of the expression of genes involved in cell growth upon expression of Tat in SK-N-MC cells. Similarly, exposure of SK-N-MC to conditioned media derived from cells expressing Tat decreased phosphorylation of MAPK and reduced the level of Egr-1 protein expression in SK-N-MC cells. Furthermore, MAPK was able to phosphorylate Puralpha, a cellular protein that plays an important role in neuronal cell function and differentiation, and this was inhibited by Tat. The ability of Puralpha to interact with a GA/GC-rich sequence positioned upstream from the transcription start site of the Egr-1 promoter provided a rationale to examine Egr-1 expression. Expression of Tat decreased NGF-induced Egr-1 levels in SK-N-MC cells and reduced binding of Puralpha to the Egr-1 promoter. All of these observations support a model where the interplay between Tat and Puralpha dysregulates the NGF pathway including the MAPK/Erk network, resulting in reduced expression and activity of Egr-1 in neuronal cells.