K29‐Linked Ubiquitination of Transcription Regulators Controls Cell Proliferation in the Unfolded Protein Response

Under endoplasmic reticulum stress, cells activate the unfolded protein response (UPR). During the UPR, the cohesin complex at the promoter of cell proliferation‐related genes undergoes K29‐linked ubiquitination, recruiting the cohesin release factor WAPL to release cohesin, leading to transcriptional downregulation and inhibition of cell growth. Abstract The ubiquitin chains perform diverse biological functions through different linkages. However, the understanding of non‐canonical K29‐linked ubiquitin chains is relatively limited. Exploring the physiological functions of K29‐linked ubiquitin chains beyond degradation is crucial for deciphering the ubiquitin chain code, which is essential for understanding cellular physiology. The unfolded protein response (UPR) serves as a crucial mechanism for cells to cope with endoplasmic reticulum stress and involves comprehensive and precise regulation. Ubiquitin, as a regulator of protein function, has potential regulatory functions other than guiding protein degradation in the UPR. Here, a close association is revealed between K29‐linked ubiquitin chains and transcriptional regulation during the UPR. After UPR induction, the K29‐linked ubiquitination of the SMC1A and SMC3 proteins in the cohesin complex increases. The transcription of cell proliferation‐related genes, such as SERTAD1 and NUDT16L1, is regulated by the K29‐linked ubiquitination of cohesin. Overall, the upregulation of K29‐linked ubiquitination of cohesin during the UPR disrupts the formation of the transcription initiation complex, resulting in the transcriptional downregulation of cell proliferation‐related genes. Under endoplasmic reticulum stress, cells activate the unfolded protein response (UPR). During the UPR, the cohesin complex at the promoter of cell proliferation-related genes undergoes K29-linked ubiquitination, recruiting the cohesin release factor WAPL to release cohesin, leading to transcriptional downregulation and inhibition of cell growth. Abstract The ubiquitin chains perform diverse biological functions through different linkages. However, the understanding of non-canonical K29-linked ubiquitin chains is relatively limited. Exploring the physiological functions of K29-linked ubiquitin chains beyond degradation is crucial for deciphering the ubiquitin chain code, which is essential for understanding cellular physiology. The unfolded protein response (UPR) serves as a crucial mechanism for cells to cope with endoplasmic reticulum stress and involves comprehensive and precise regulation. Ubiquitin, as a regulator of protein function, has potential regulatory functions other than guiding protein degradation in the UPR. Here, a close association is revealed between K29-linked ubiquitin chains and transcriptional regulation during the UPR. After UPR induction, the K29-linked ubiquitination of the SMC1A and SMC3 proteins in the cohesin complex increases. The transcription of cell proliferation-related genes, such as SERTAD1 and NUDT16L1, is regulated by the K29-linked ubiquitination of cohesin. Overall, the upregulation of K29-linked ubiquitination of cohesin during the UPR disrupts the formation of the transcription initiation complex, resulting in the transcriptional downregulation of cell proliferation-related genes. Advanced Science, Volume 12, Issue 42, November 13, 2025.