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SLFN11 Induces Apoptosis Through Ribosome Biogenesis Impairment

ABSTRACT: Impairment of ribosome biogenesis (RiBi) is triggered by the inhibition of rRNA synthesis and processing and leads to various biological effects. We discovered that Schlafen 11 (SLFN11)-dependent sensitization to replication stress produced by chemotherapeutic drugs induces RiBi impairment. Mechanistically, SLFN11 alters the chromatin structure of rDNA in response to replication stress, sequestering RNA polymerase I on chromatin while inhibiting rRNA synthesis and nucleolar R-loop formation. SLFN11-induced RiBi impairment inhibits translation overall, depleting extremely short-lived proteins, particularly MCL1, an ubiquitous anti-apoptotic protein. Consequently, SLFN11 activates apoptosis in an MCL1-dependent but TP53-independent manner. Comparable effects were observed with RNA polymerase I inhibitors and other RiBi inhibitory conditions regardless of SLFN11. These findings were validated across 34 diverse human cancer cell lines. Thus, we demonstrate that RiBi impairment is a robust inactivator of MCL1 and an activator of apoptosis and identify an additional mechanism by which SLFN11 sensitizes cancer cells to chemotherapeutic agents.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Junko Murai

PROVIDER: PXD052471 | JPOST Repository | Thu May 22 00:00:00 BST 2025

REPOSITORIES: jPOST

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			Action	DRS
	230313mm_003_CEM_Control_%231a.d.zip	Other
	230313mm_004_CEM_CPT-100nM_6hr_%232a.d.zip	Other
	230313mm_005_CEM_Chk1-i-100nM_6hr_%233a.d.zip	Other
	230313mm_007_CB45_Control_%235a.d.zip	Other
	230313mm_008_CB45_CPT-100nM_6hr_%236a.d.zip	Other

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