title: Emerging role of RNA•DNA hybrids in C9orf72-linked neurodegeneration.
abstract: RNA plays an active role in structural polymorphism of the genome through the formation of stable RNA•DNA hybrids (R-loops). R-loops can modulate normal physiological processes and are also associated with pathological conditions, such as those related to nucleotide repeat expansions. A guanine-rich hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) has been linked to a spectrum of neurological conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we discuss the possible roles, both locally and genome-wide, of R-loops that may arise from the C9orf72 hexanucleotide repeat. R-loops have the potential to influence the pathological processes identified in many repeat expansion diseases, such as repeat instability, transcriptional dysregulation, epigenetic modification, and antisense-mediated gene regulation. We propose that, given the wide-ranging consequences of R-loops in the cell, these structures could underlie multiple pathological processes in C9orf72-linked neurodegeneration.
authors.affiliation: a Department of Biochemistry and Molecular Biology; Bloomberg School of Public Health ; Johns Hopkins University ; Baltimore , MD USA.
authors.forename: Jiou
authors.initials: J
authors.lastname: Wang
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Haeusler
authors.forename: Eric A J
authors.initials: EA
authors.lastname: Simko
mesh_terms: D000073885:C9orf72 Protein; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D042622:DNA Repeat Expansion / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D011506:Proteins / Q000235:genetics*; D012313:RNA / Q000235:genetics / Q000378:metabolism*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D012313:RNA; D004247:DNA
keywords: ALS; ALS, amyotrophic lateral sclerosis; AOA2, ataxia with oculomotor apraxia type 2; C9orf72; C9orf72, chromosome 9 open reading frame 72; CpG island, cytosine-phosphate-guanine island; FTD; FTD, frontotemporal dementia; G-quadruplex; HRE, hexanucleotide repeat expansion; R-loop; RNA; antisense; histone methylation