The Importance of Satellite Sequence Repression for Genome Stability

Abstract

Up to two-thirds of eukaryotic genomes consist of repetitive sequences, which include both transposable elements and tandemly arranged simple or satellite repeats. Whereas extensive progress has been made toward understanding the danger of and control over transposon expression, only recently has it been recognized that DNA damage can arise from satellite sequence transcription. Although the structural role of satellite repeats in kinetochore function and end protection has long been appreciated, it has now become clear that it is not only these functions that are compromised by elevated levels of transcription. RNA from simple repeat sequences can compromise replication fork stability and genome integrity, thus compromising germline viability. Here we summarize recent discoveries on how cells control the transcription of repeat sequence and the dangers that arise from their expression. We propose that the link between the DNA damage response and the transcriptional silencing machinery may help a cell or organism recognize foreign DNA insertions into an evolving genome.

A conserved function for pericentromeric satellite DNA

“…Moreover, highly divergent satellite DNA sequences even among closely related species has led to the idea that satellite DNA does not serve a conserved function and is mostly a selfish element or junk ( Doolittle and Sapienza, 1980 ; Walker, 1971 ). Pericentromeric satellite DNA repeats are proposed to be sources of genomic instability, as their misexpression is associated with the formation of genotoxic R-loops and DNA damage ( Zhu et al, 2011 ; Zeller et al, 2016 ; Zeller and Gasser, 2017 ). Most studies on pericentromeric heterochromatin have focused on the mechanisms to repress satellite DNA transcription, and accordingly, a clear rationale for the existence of most pericentromeric satellite DNA is still lacking.…”

Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice

“…Facultative heterochromatin (fHC) comprises regions containing genes that are differentially expressed throughout development and/or differentiation and which then become silenced. Conversely, constitutive heterochromatin (cHC) is largely formed at pericentromeres and telomeres that are gene-poor regions that mainly contain repetitive sequences, including transposable elements as well as tandemly arranged simple or satellite repeats [20,22]. To regulate the compaction of HC, the nucleosomal histones in the HC regions are enriched by specific epigenetic marks.…”

A conserved function for pericentromeric satellite DNA

“…The function of chromocenters, as well as that of satellite DNA, has remained enigmatic, even though cytological association of pericentromeric satellite DNA into chromocenters was identified almost 50 years ago (Pardue and Gall, 1970). Pericentromeric heterochromatin has most often been studied and discussed in the context of how to maintain its heterochromatic, repressed nature (Nishibuchi and Déjardin, 2017), based on the assumption that the underlying sequences are mostly selfish, which have negative phenotypic consequences when derepressed in cells (Zeller and Gasser, 2017).…”

“…Moreover, highly divergent satellite DNA sequences even among closely-related species has led to the idea that satellite DNA does not serve a conserved function and is mostly a selfish element or junk (Doolittle and Sapienza, 1980; Walker, 1971). Pericentromeric satellite DNA repeats are proposed to be sources of genomic instability, as their misexpression is associated with the formation of genotoxic R-loops and DNA damage (Zeller et al, 2016; Zhu et al, 2011; Zeller and Gasser, 2017). Most studies on pericentromeric heterochromatin have focused on the mechanisms to repress satellite DNA, and accordingly, a rationale for the very existence of pericentromeric satellite DNA is still lacking.…”