A Unifying Model for Cohesinopathies and Thalidomide Teratogenicity

Abstract Roberts Syndrome (RBS) and Cornelia de Lange Syndrome (CdLS) are developmental conditions in humans collectively termed cohesinopathies. RBS and CdLS result in limb malformation, craniofacial abnormalities, cognitive disabilities, and defects in numerous internal organs, such as the GI tract and cardiac systems. Cohesinopathies arise due to improper cohesin function. Cohesin is a complex that plays a role in DNA tethering both in cis (along the same strand of DNA) and trans (between sister chromatids) mechanisms. DNA tethering is crucial for sister chromatid cohesin, DNA condensation, DNA repair, and transcriptional regulation. While the gene mutations resulting in cohesinopathies are well established, the downstream impacts of such mutations are largely unknown. Interestingly, the developmental defects arising from RBS and CdLS are highly similar to those due to thalidomide exposure during pregnancy. Thalidomide was a popular drug used to treat morning sickness in the late 1950s. Thalidomide exposure led to approximately 10,000 babies being born with severe developmental abnormalities. In this case, thalidomide blocks Cullin4 Ring Ligase (CRL4), a ubiquitin ligase that clears embryos of factors that adversely impact development. The downstream targets of CRL4 that lead to organ malformations are still elusive. Yet, thalidomide is an immunomodulatory (IMiD) drug that has proven effective in treatments of Hansen's Disease, leprosy, and myeloma. Thus, understanding the molecular mechanisms through which thalidomide acts is essential for drug discovery and new therapies. Here, we investigate the role of cohesin in regulating the thalidomide target, CRL4. First, we report findings that the cohesin pathway impacts gene regulation of an essential CRL4 component. Second, we identify downstream targets of the cohesin/CRL4 axis that lead to organ malformation. These findings provide a unified molecular mechanism shared by thalidomide poisoning, and genetic outcomes that produce RBS and CdLS. This study provides a model to study multi-spectrum syndromes previously believed to be unrelated to each other. This research can help advance treatment options for rare diseases, as they may not be so rare after all.