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

Ália dos Santos, Daniel E. Rollins, Yukti Hari-Gupta, Hannah McArthur, Mingxue Du, Sabrina Yong Zi Ru, Kseniia Pidlisna, Ane Stranger, Faeeza Lorgat, Danielle Lambert, Ian Brown, Kevin Howland, Jesse Aaron, Lin Wang, Peter J. I. Ellis, Teng-Leong Chew, Marisa Martin-Fernandez, Alice L. B. Pyne and Christopher P. Toseland ()
Additional contact information
Ália dos Santos: University of Sheffield
Daniel E. Rollins: University of Sheffield
Yukti Hari-Gupta: University of Kent
Hannah McArthur: University of Kent
Mingxue Du: University of Sheffield
Sabrina Yong Zi Ru: University of Kent
Kseniia Pidlisna: University of Kent
Ane Stranger: University of Kent
Faeeza Lorgat: University of Sheffield
Danielle Lambert: University of Sheffield
Ian Brown: University of Kent
Kevin Howland: University of Kent
Jesse Aaron: HHMI Janelia Research Campus
Lin Wang: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell, Didcot
Peter J. I. Ellis: University of Kent
Teng-Leong Chew: HHMI Janelia Research Campus
Marisa Martin-Fernandez: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell, Didcot
Alice L. B. Pyne: University of Sheffield
Christopher P. Toseland: University of Sheffield

Nature Communications, 2023, vol. 14, issue 1, 1-24

Abstract: Abstract NDP52 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.

Date: 2023
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DOI: 10.1038/s41467-023-38572-9

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