Long noncoding RNA LINP1: scaffolding non-homologous end joining.

A Sakthianandeswaren,Om Sieber,S Liu

doi:10.1038/cddiscovery.2016.59

Abstract

Non-homologous end joining (NHEJ) is a principal pathway of DNA double-strand break (DSB) repair in mammalian cells,1 but is also involved in assembly of antigen receptor genes and telomere maintenance.2,3 Loss of NHEJ function can result in chromosome instability promoting malignant transformation, in particular when other cellular safeguards are compromised. Inherited NHEJ defects underlie radiosensitive severe combined immunodeficiency. NHEJ is initiated by binding of Ku70–Ku80 heterodimers to both ends of a DNA break, followed by recruitment of catalytic subunits of DNA-dependent protein kinase (DNA-PKcs) to form juxtaposed DNA-PK holoenzymes which join the ends in a synaptic complex. Cohesive blunt DNA ends can be joined directly by the XFL-XRCC4-DNA ligase IV complex, but in many cases DNA ends contain damaged bases or DNA backbone sugars that require processing before ligation. End processing may involve nucleases such as Artemis, DNA polymerases and polynucleotide kinase among other enzymes.4,5

Highlights

Non-homologous end joining (NHEJ) is a principal pathway of DNA double-strand break (DSB) repair in mammalian cells,[1] but is involved in assembly of antigen receptor genes and telomere maintenance.[2,3] Loss of NHEJ function can result in chromosome instability promoting malignant transformation, in particular when other cellular safeguards are compromised
LINP1 knockdown in triple-negative breast cancers (TNBCs) cells resulted in reduced DNA break repair in comet, γ-H2AX foci and NHEJ reporter assays
Analyses of chromatin-associated NHEJ complexes post-irradiation with LINP1, Ku80 or DNA-PKcs knockdown indicated that recognition of DSBs by Ku70–Ku80 resulted in recruitment of LINP1 and DNA-PKcs, with LINP1 enhancing the Ku80–DNA-PKcs interaction

Summary

Introduction

Non-homologous end joining (NHEJ) is a principal pathway of DNA double-strand break (DSB) repair in mammalian cells,[1] but is involved in assembly of antigen receptor genes and telomere maintenance.[2,3] Loss of NHEJ function can result in chromosome instability promoting malignant transformation, in particular when other cellular safeguards are compromised. LINP1 knockdown in TNBC cells resulted in reduced DNA break repair in comet, γ-H2AX foci and NHEJ reporter assays. Overexpression of LINP1 in ER+ BC cells increased NHEJ activity. EGF signaling was identified as a positive regulator of LINP1 expression.

Results

Conclusion