biostudies-literatureJiang MMedical Scientific Research Foundation of Guagndong ProvinceSZU Top Ranking Project "B&RsacFMS"SZU Top Ranking ProjectChina Postdoctoral Science Foundation ( )SZU Top Ranking Project "B&RsacFMS"China Postdoctoral Science FoundationNational Natural Science Foundation of ChinaNational Nature Science Foundation of ChinaShenzhen Science and Technology Program278-309https://www.ebi.ac.uk/biostudies/studies/S-EPMC12759081biostudies-literatureUnknown45(1)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.The EMBO journalS-phase PARylation of microprotein RSMC enhances the function of Sororin in sister chromatid cohesion.PMC12759081JCYJ2024081314370100332161133015868/0000080208A20243422101039KQTD20240729102249044860/000002102024M752102JCYJ2024081314300100332300074RCBS2023121109051601732101039Xia YZhang JHe JJiang MChen CGong YYdyrys AWang LHou WLi ZMiao YLou HZhong HDu LLXu XCao QfalseS-phase PARylation of microprotein RSMC enhances the function of Sororin in sister chromatid cohesion.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.2026-01-01T00:00:00Z2026 Jan2026-06-06T10:42:12.375Z2026-05-29T03:12:27.042ZS-EPMC127590814126121610.1038/s44318-025-00641-8