Autophagy receptor NDP52 alters DNA conformation to modulate RNA polymerase II transcription

Author:

dos Santos ÁliaORCID,Rollins Daniel E.,Hari-Gupta Yukti,McArthur HannahORCID,Du Mingxue,Ru Sabrina Yong Zi,Pidlisna Kseniia,Stranger Ane,Lorgat Faeeza,Lambert DanielleORCID,Brown IanORCID,Howland KevinORCID,Aaron JesseORCID,Wang LinORCID,Ellis Peter J. I.ORCID,Chew Teng-LeongORCID,Martin-Fernandez MarisaORCID,Pyne Alice L. B.ORCID,Toseland Christopher P.ORCID

Abstract

AbstractNDP52 is an autophagy receptor involved in the recognition and degradation of invading pathogens and damaged organelles. Although NDP52 was first identified in the nucleus and is expressed throughout the cell, to date, there is no clear nuclear functions for NDP52. Here, we use a multidisciplinary approach to characterise the biochemical properties and nuclear roles of NDP52. We find that NDP52 clusters with RNA Polymerase II (RNAPII) at transcription initiation sites and that its overexpression promotes the formation of additional transcriptional clusters. We also show that depletion of NDP52 impacts overall gene expression levels in two model mammalian cells, and that transcription inhibition affects the spatial organisation and molecular dynamics of NDP52 in the nucleus. This directly links NDP52 to a role in RNAPII-dependent transcription. Furthermore, we also show that NDP52 binds specifically and with high affinity to double-stranded DNA (dsDNA) and that this interaction leads to changes in DNA structure in vitro. This, together with our proteomics data indicating enrichment for interactions with nucleosome remodelling proteins and DNA structure regulators, suggests a possible function for NDP52 in chromatin regulation. Overall, here we uncover nuclear roles for NDP52 in gene expression and DNA structure regulation.

Funder

RCUK | Medical Research Council

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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