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Human SKI component SKIV2L regulates telomeric DNA-RNA hybrids and prevents telomere fragility

ABSTRACT: Super killer (SKI) complex is a well-known cytoplasmic 3′ to 5′ mRNA decay complex that functions with the exosome to degrade excessive and aberrant mRNAs. Recently, SKIV2L, the 3′ to 5′ RNA helicase of the human SKI (hSKI) complex has been implicated with the extraction of mRNA at stalled ribosomes, tackling aberrant translation. Here, we show that SKIV2L and TTC37 of the hSKI complex are present within the nucleus, localise on chromatin and at some telomeres during the G2 cell cycle phase. In cells, SKIV2L prevents telomere replication stress shown as fragile telomeres and increases the stability of telomere DNA-RNA hybrids in G2 of the cell cycle whereas its absence decreases the amount of those structures. We further demonstrate that purified hSKI complex binds telomeric DNA and RNA substrates in vitro. Moreover, SKIV2L association with telomeres is dependent on DNA-RNA hybrids but its helicase activity is dispensable for its telomeric function. Taken together, our results provide a nuclear function for SKIV2L of the hSKI complex in overcoming replication stress at telomeres mediated by its recruitment to DNA-RNA hybrid structures in G2 and thus maintaining telomere stability.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Line Cell

SUBMITTER: Alex Montoya

LAB HEAD: Dr Pavel Shliaha

PROVIDER: PXD046955 | Pride | 2024-10-03

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	Swissprot_human_20170202.fasta	Fasta
	b025p021_ASCR_TR01.raw	Raw
	b025p021_ASCR_TR02.raw	Raw
	b025p021_ASTelo_TR01.raw	Raw
	b025p021_ASTelo_TR02.raw	Raw

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Project description:Genomic instability associated with DNA replication stress is linked to cancer and genetic pathologies in humans. If not properly regulated, replication stress, such as fork stalling and collapse, can be induced at natural replication impediments present throughout the genome. The fork protection complex (FPC) is thought to play a critical role in stabilizing stalled replication forks at several known replication barriers including eukaryotic rDNA genes and the fission yeast mating-type locus. However, little is known about the role of the FPC at other natural impediments including telomeres. Telomeres are considered to be difficult to replicate due to the presence of repetitive GT-rich sequences and telomere-binding proteins. However, the regulatory mechanism that ensures telomere replication is not fully understood. Here, we report the role of the fission yeast Swi1/Timeless, a subunit of the FPC, in telomere replication. Loss of Swi1 causes telomere shortening in a telomerase-independent manner. Our epistasis analyses suggest that heterochromatin and telomere-binding proteins are not major impediments for telomere replication in the absence of Swi1. Instead, repetitive DNA sequences impair telomere integrity in swi1Î mutant cells, leading to the loss of repeat DNA. In the absence of Swi1, telomere shortening is accompanied with an increased recruitment of Rad52 recombinase and more frequent amplification of telomere/subtelomeres, reminiscent of tumor cells that utilize the alternative lengthening of telomeres pathway (ALT) to maintain telomeres. These results suggest that Swi1 ensures telomere replication by suppressing recombination and repeat instability at telomeres. Our studies may also be relevant in understanding the potential role of the FPC in regulation of telomere stability in cancer cells. Genome-wide distributions of Rad52 in wild type and in swi1 deletion in fission yeast The'SP1173_WT ChIP-seq' is an input sample (non-tagged data).

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Human SKI component SKIV2L regulates telomeric DNA-RNA hybrids and prevents telomere fragility

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