Vol 49(2015) N 1 p. 86-98; DOI 10.1134/S0026893315010094
N.V. Maluchenko1*, O.I. Kulaeva1,2, E.Yu. Kotova2, A.A. Chupyrkina1, D.V. Nikitin1,3, M.P. Kirpichnikov1, V.M. Studitsky1,2
Molecular mechanisms of transcriptional regulation by poly(ADP-ribose) polymerase 11Biological Faculty, Moscow State University, Moscow, 119991 Russia
2 Fox Chase Cancer Center, Philadelphia, PA, 19111-2497 USA
3Skriabin Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences, Pushchino, Moscow Region, 142290 Russia
Received - 2014-09-15; Accepted - 2014-09-15
Poly-ADP-ribosylation is a covalent posttranslational modification of nuclear proteins that plays a key role in the immediate cell response to genotoxic stress. Poly(ADP-ribose) polymerases (PARPs) synthesize long and branched ADP-ribose polymers on acceptor regulatory proteins, thereby changing their activity. Poly-ADP metabolism regulates DNA repair, the cell cycle, replication, cell senescence and death, a remodeling of the chromatin structure, and gene transcription. PARP1 is one of the most common nuclear proteins and is responsible for producing ~90% of all ADP-ribose polymers in the cell. PARP1 inhibitors are promising as anti-tumor agents. At the same time, current inhibitors targeting the catalytic domain of PARP1 have a number of side effects. Considering the potential benefits PARP1 inhibitors may offer for treating many diseases, it is necessary to develop new strategies of PARP1 inhibition. PARP1 has a modular structure and possesses catalytic, transcription, and DNA-binding activities. The review focuses primarily on the role PARP1 plays in regulating transcription. The structure and functional organization of PARP1 and multiple pathways of the PARP1-dependent transcriptional regulation at the levels of chromatin remodeling, DNA methylation, and transcription are considered in detail. Studying the molecular mechanisms that regulate these processes can provide a basis for a search and design of new PARP1 inhibitors.
PARP1, poly-ADP-ribosylation, transcription, chromatin