Abstract
Sororin is essential for establishing sister chromatid cohesion concurrently with DNA replication in metazoans. Although acetylation of the cohesin subunit SMC3 by ESCO1/2 is necessary for Sororin recruitment, it is by itself not sufficient. Here, we demonstrate that DNA replication-coupled Poly(ADP-Ribose) Polymerase (PARP) activity is an additional prerequisite in human cells. During normal S-phase, PARP1 PARylates a microprotein encoded by the alternative ORF C11ORF98, which we designate RSMC (28S rRNA/ribosome and Sororin micro-cofactor). This PARylation strengthens the interaction of RSMC with Sororin, enhancing both chromatin recruitment and anti-Wapl activity of Sororin in concert with SMC3 acetylation. Notably, overexpression of RSMC is able to rescue cohesion defects induced by the PARP inhibitor olaparib. These findings highlight understudied microproteins as critical regulators of fundamental cellular processes, such as sister chromatid cohesion.