Chromatin-associated Orphan snoRNA Regulates DNA damage-mediated differentiation via a Non-canonical Complex
Description
Small nucleolar RNAs (snoRNAs) are commonly acknowledged as a class of homogeneous non-coding RNAs and guide ribosomal RNA modifications. However, snoRNAs referred as orphan ones have largely unknown functions. Here, we systematically profiled the chromatin-associated snoRNAs (casnoRNAs) in mammalian cells, and identified a subgroup of orphan casnoRNAs responding to DNA damage stress among which SNORA73 showed the most marked reduction in chromatin enrichment. Downregulated SNORA73 maintained cancer genome stability and differentiation block in hematopoietic malignancy. Mechanically, casnoRNA SNORA73’s 5’ end non-canonical structure was critical for its function and binding to poly (ADP-ribose) polymerase 1 (PARP1). SNORA73 inhibited PARP1 auto-PARylation to affect cancer genome stability by forming a small nucleolar ribonucleoprotein (snoRNP) with PARP1 and canonical H/ACA proteins DKC1/NHP2. This revealed the role of an orphan snoRNA serving as casnoRNA and highlights a link between non-canonical structure of snoRNA and their functional diversity.