Structural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine

Abstract Cytarabine (AraC) is an essential chemotherapeutic for acute myeloid leukemia (AML) and resistance to this drug is a major cause of treatment failure. AraC is a nucleoside analog that differs from 2′-deoxycytidine only by the presence of an additional hydroxyl group at the C2′ position of t...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Olga Rechkoblit, Jayati Roy Choudhury, Angeliki Buku, Louise Prakash, Satya Prakash, Aneel K. Aggarwal
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fc4ac48cac464dccbd0b27802d40046f
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:fc4ac48cac464dccbd0b27802d40046f
record_format	dspace
spelling	oai:doaj.org-article:fc4ac48cac464dccbd0b27802d40046f2021-12-02T15:08:50ZStructural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine10.1038/s41598-018-30796-w2045-2322https://doaj.org/article/fc4ac48cac464dccbd0b27802d40046f2018-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-30796-whttps://doaj.org/toc/2045-2322Abstract Cytarabine (AraC) is an essential chemotherapeutic for acute myeloid leukemia (AML) and resistance to this drug is a major cause of treatment failure. AraC is a nucleoside analog that differs from 2′-deoxycytidine only by the presence of an additional hydroxyl group at the C2′ position of the 2′-deoxyribose. The active form of the drug AraC 5′-triphosphate (AraCTP) is utilized by human replicative DNA polymerases to insert AraC at the 3′ terminus of a growing DNA chain. This impedes further primer extension and is a primary basis for the drug action. The Y-family translesion synthesis (TLS) DNA polymerase η (Polη) counteracts this barrier to DNA replication by efficient extension from AraC-terminated primers. Here, we provide high-resolution structures of human Polη with AraC incorporated at the 3′-primer terminus. We show that Polη can accommodate AraC at different stages of the catalytic cycle, and that it can manipulate the conformation of the AraC sugar via specific hydrogen bonding and stacking interactions. Taken together, the structures provide a basis for the ability of Polη to extend DNA synthesis from AraC terminated primers.Olga RechkoblitJayati Roy ChoudhuryAngeliki BukuLouise PrakashSatya PrakashAneel K. AggarwalNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-9 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Olga Rechkoblit Jayati Roy Choudhury Angeliki Buku Louise Prakash Satya Prakash Aneel K. Aggarwal Structural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine
description	Abstract Cytarabine (AraC) is an essential chemotherapeutic for acute myeloid leukemia (AML) and resistance to this drug is a major cause of treatment failure. AraC is a nucleoside analog that differs from 2′-deoxycytidine only by the presence of an additional hydroxyl group at the C2′ position of the 2′-deoxyribose. The active form of the drug AraC 5′-triphosphate (AraCTP) is utilized by human replicative DNA polymerases to insert AraC at the 3′ terminus of a growing DNA chain. This impedes further primer extension and is a primary basis for the drug action. The Y-family translesion synthesis (TLS) DNA polymerase η (Polη) counteracts this barrier to DNA replication by efficient extension from AraC-terminated primers. Here, we provide high-resolution structures of human Polη with AraC incorporated at the 3′-primer terminus. We show that Polη can accommodate AraC at different stages of the catalytic cycle, and that it can manipulate the conformation of the AraC sugar via specific hydrogen bonding and stacking interactions. Taken together, the structures provide a basis for the ability of Polη to extend DNA synthesis from AraC terminated primers.
format	article
author	Olga Rechkoblit Jayati Roy Choudhury Angeliki Buku Louise Prakash Satya Prakash Aneel K. Aggarwal
author_facet	Olga Rechkoblit Jayati Roy Choudhury Angeliki Buku Louise Prakash Satya Prakash Aneel K. Aggarwal
author_sort	Olga Rechkoblit
title	Structural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine
title_short	Structural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine
title_full	Structural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine
title_fullStr	Structural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine
title_full_unstemmed	Structural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine
title_sort	structural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/fc4ac48cac464dccbd0b27802d40046f
work_keys_str_mv	AT olgarechkoblit structuralbasisforpolymeraseēpromotedresistancetotheanticancernucleosideanalogcytarabine AT jayatiroychoudhury structuralbasisforpolymeraseēpromotedresistancetotheanticancernucleosideanalogcytarabine AT angelikibuku structuralbasisforpolymeraseēpromotedresistancetotheanticancernucleosideanalogcytarabine AT louiseprakash structuralbasisforpolymeraseēpromotedresistancetotheanticancernucleosideanalogcytarabine AT satyaprakash structuralbasisforpolymeraseēpromotedresistancetotheanticancernucleosideanalogcytarabine AT aneelkaggarwal structuralbasisforpolymeraseēpromotedresistancetotheanticancernucleosideanalogcytarabine
_version_	1718388038340444160

Structural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine

Ejemplares similares