RRC ID 56217
Author Saldi TK, Gonzales P, Garrido-Lecca A, Dostal V, Roberts CM, Petrucelli L, Link CD.
Title The Caenorhabditis elegans Ortholog of TDP-43 Regulates the Chromatin Localization of the Heterochromatin Protein 1 Homolog HPL-2.
Journal Mol Cell Biol
Abstract TDP-1 is the Caenorhabditis elegans ortholog of mammalian TDP-43, which is strongly implicated in the etiology of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We discovered that deletion of the tdp-1 gene results in enhanced nuclear RNA interference (RNAi). As nuclear RNAi in C. elegans involves chromatin changes moderated by HPL-2, a homolog of heterochromatin protein 1 (HP1), we investigated the interaction of TDP-1 and HPL-2. We found that TDP-1 and HPL-2 interact directly and that loss of TDP-1 dramatically alters the chromatin association of HPL-2. We showed previously that deletion of the tdp-1 gene results in transcriptional alterations and the accumulation of double-stranded RNA (dsRNA). These molecular changes are replicated in an hpl-2 deletion strain, consistent with HPL-2 acting in consort with TDP-1 to modulate these aspects of RNA metabolism. Our observations identify novel mechanisms by which HP1 homologs can be recruited to chromatin and by which nuclear depletion of human TDP-43 may lead to changes in RNA metabolism that are relevant to disease.
Volume 38(15)
Published 2018-8-1
DOI 10.1128/MCB.00668-17
PII MCB.00668-17
PMID 29760282
PMC PMC6048318
MeSH Alternative Splicing Animals Animals, Genetically Modified Caenorhabditis elegans / genetics* Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Nucleus / metabolism Chromatin / metabolism Chromobox Protein Homolog 5 Chromosomal Proteins, Non-Histone / deficiency Chromosomal Proteins, Non-Histone / genetics Chromosomal Proteins, Non-Histone / metabolism* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Gene Deletion Genes, Helminth Humans Neurodegenerative Diseases / etiology Neurodegenerative Diseases / genetics Neurodegenerative Diseases / metabolism RNA Interference RNA, Helminth / genetics RNA, Helminth / metabolism RNA-Binding Proteins / genetics RNA-Binding Proteins / metabolism*
IF 3.735
Times Cited 4
C.elegans tm1116 tm1489