MiR-502 is the first reported miRNA simultaneously targeting two components of the classical non-homologous end joining (C-NHEJ) in pancreatic cell lines

Agnieszka Smolinska,Julia Swoboda,Wojciech Fendler,Markus M Lerch,Matthias Sendler,Patryk Moskwa

doi:10.1016/j.heliyon.2020.e03187

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Acquired inherited and/or somatic mutations drive its development. In order to prevent the formation of these mutations, precise and immediate repair of any DNA damage is indispensable. Non-homologous end-joining (NHEJ) is the key mechanism of DNA double-strand break repair. Here, we report that miR-502 targets two components in pancreatic cell lines, Ku70 and XLF of the C-NHEJ. Interestingly, we also observed an attenuated cell cycle response to gamma ionizing radiation (γ-IR) via diminished phosphorylation of checkpoint kinase 1 (Chk1) on serine 345 in these cell lines. Altogether, pancreatic cells showed increased susceptibility to γ-IR via direct inhibition of DNA double-strand break repair and attenuation of the cell cycle response.

Highlights

Pancreatic cancer is the 4th leading cause of cancer-related deaths among all cancers
Plates were scanned and quantified by ImageJ. Both DNA repair pathways, homologous recombination (HR) and Non-homologous end-joining (NHEJ), are in turn actively regulated throughout the cell cycle [7]
We postulated that miRNAs constitute a possible mechanism controlling the C-NHEJ activity and, their expression is expected to change throughout the cell cycle

Summary

Introduction

Pancreatic cancer is the 4th leading cause of cancer-related deaths among all cancers. Formulation of new chemotherapeutic strategies, and surgical development, only very moderate progress has been achieved over the past decades and, pancreatic cancer is expected by 2030 to become the second leading cause of cancer-related deaths [1]. Inherited mutations of DNA repair genes such as BRCA1, BRCA2, PALB2, FANCC, FANCG and ATM have been well established in the genesis of pancreatic cancer [2]. These genes are key players in homologous recombination (HR), the high fidelity mechanism of DSB repair. PanINs are believed to progress stepwise to overt pancreatic cancer due to the sequential accumulation of acquired mutations such as TP53, SMAD4 and CDKN2A [3, 4]

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