PrimPol Variant V102A with Altered Primase and Polymerase Activities.

Autor: Boldinova EO; National Research Center 'Kurchatov Institute', Kurchatov sq. 2, 123182 Moscow, Russia; Institute of Gene Biology, Russian Academy of Sciences, Vavilova 34 / 5, 119334 Moscow, Russia., Baranovskiy AG; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA., Filina YV; 'Translational Oncology' Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kremlevskaya 18, 420008 Kazan, Russia., Miftakhova RR; 'Translational Oncology' Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kremlevskaya 18, 420008 Kazan, Russia., Shamsutdinova YF; Chemotherapy Department №1, Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Tatarstan Named After Prof. M.Z. Sigal, Sibirskiy trakt 29, 420029 Kazan, Russia., Tahirov TH; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA., Makarova AV; National Research Center 'Kurchatov Institute', Kurchatov sq. 2, 123182 Moscow, Russia; Institute of Gene Biology, Russian Academy of Sciences, Vavilova 34 / 5, 119334 Moscow, Russia. Electronic address: amakarova-img@yandex.ru.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2024 May 01; Vol. 436 (9), pp. 168542. Date of Electronic Publication: 2024 Mar 15.
DOI: 10.1016/j.jmb.2024.168542
Abstrakt: PrimPol is a human DNA primase-polymerase which restarts DNA synthesis beyond DNA lesions and non-B DNA structures blocking replication. Disfunction of PrimPol in cells leads to slowing of DNA replication rates in mitochondria and nucleus, accumulation of chromosome aberrations, cell cycle delay, and elevated sensitivity to DNA-damaging agents. A defective PrimPol has been suggested to be associated with the development of ophthalmic diseases, elevated mitochondrial toxicity of antiviral drugs and increased cell resistance to chemotherapy. Here, we describe a rare missense PrimPol variant V102A with altered biochemical properties identified in patients suffering from ovarian and cervical cancer. The Val102 to Ala substitution dramatically reduced both the primase and DNA polymerase activities of PrimPol as well as specifically decreased its ability to incorporate ribonucleotides. Structural analysis indicates that the V102A substitution can destabilize the hydrophobic pocket adjacent to the active site, affecting dNTP binding and catalysis.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: