SLFN11 restricts escape from telomere crisis to prevent alternative lengthening of telomeres
Authors list
Sandra Segura-Bayona Valerie Borel Tyler Stanage Marija Maric Melanie Walter Rafaela A Oliveira Shudong Li Aurora Idilli Martina Peritore Graeme Hewitt Maarten Hekkelman Daniel Snell Sam T Jones Chris Cheshire Areda Elezi Probir Chakravarty Richard Mitter Anna Mikolajczak Harriet E Gee Emma Nye Roderick J O'Sullivan Aatur D Singhi Thijn R Brummelkamp Anthony J Cesare Simon BoultonThis article is a preprint. Preprints have not been peer-reviewed.
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Abstract
The tRNA nuclease SLFN11 is epigenetically silenced in ∼50% of treatment-naive tumours and is the strongest predictor of chemoresistance but why it is frequently inactivated in cancer is unknown. To acquire immortality, cancer cells can activate alternative lengthening of telomeres (ALT), typically accompanied by ATRX loss. Here, we implicate SLFN11 in sensing telomere replication stress, triggering eradication of ATRX deficient cells prior to ALT establishment. Whereas progressive telomere shortening of cells lacking telomerase and ATRX leads to telomere crisis and cell death, SLFN11 loss confers tolerance to PML-BLM dependent ALT intermediates, permitting emergence of ALT survivors. We propose that during tumorigenesis SLFN11 inactivation is selected as means to tolerate endogenous replication stress following telomere crisis, leading to the development of therapy resistant tumours before treatment.
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bioRxiv
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