SLFN11 puts the brakes on Alternative lengthening of telomeres

Abstract

Alternative lengthening of telomeres (ALT) is a homologous recombination-dependent mechanism maintaining telomere length in approximately 10-15% of all cancers that are telomerase (TERT) negative. ALT is most prominent in osteosarcoma. Although many ALT cells feature loss of the ATRX/DAXX chromatin remodeling complex, ATRX/DAXX deficiency alone is insufficient to trigger ALT. Here, we provide evidence that Schlafen 11 (SLFN11) acts as a suppressor of the telomeric ALT pathway. TERT-negative osteosarcoma U2-OS (ALT) cells, that normally lack SLFN11 expression, show SLFN11 localization to telomeres upon doxycycline-induced SLFN11 expression. This re-expression markedly suppresses ALT activity, as evidenced by reduced ALT-associated PML bodies (APBs) and decreased levels of Telomeric Repeat-containing RNA (TERRA). SLFN11 re-expression also attenuates the telomeric DNA damage response (DDR) and induces telomere destabilization in ALT cells. Furthermore, SLFN11 suppresses ALT induction in ATRX-depleted prostate carcinoma DU145 cells. Collectively, our findings identify SLFN11 as a negative telomeric regulator of the ALT pathway, indicating that its loss, together with ATRX/DAXX inactivation, contributes to ALT activation.