Cohesion factor mutations are firmly situated at the nexus of birth defects, severe cognitive impairment, cell aneuploidy and cancer. Presently, mutations within different classes of cohesion factors (cohesin tethers, deposition complex and establishment factors) are thought to result in different developmental maladies: cohesin and deposition mutations give rise to Cornelia de Lange Syndrome (CdLS) while establishment mutations give rise to Roberts Syndrome (RBS). The molecular bases for these birth defects are also considered to be separate, despite the very similar nature of these multispectrum maladies: CdLS arising from transcription dysregulation, RBS arising from apoptotic loss of progenitor cells. We first identified and now have characterized a third class of cohesion factors - Chl1 DNA helicase. Mutations in human Chl1 (ChlR1/DDX11) leads to another multispectrum developmental disorder, termed Warsaw Breakage Syndrome (WABS) that share many features (cognitive impairment, cranio/facial abnormalities, growth retardation, deafness, heart defects and extremity impairments) found in both CdLS and RBS. In the course of our studies, we found that Chl1 both interacts with establishment factor Eco1 and is required for the recruitment to DNA of both cohesin and cohesin deposition complex. From this, we hypothesize that WABS, CdLS and RBS are in reality a single disease state differentiated only by penetrance and severity. Currently, Chl1 DNA helicase is uniquely placed as the founding link through which all three maladies can be studied in the aggregate. Despite the critical (and clinical) nature of Chl1, little is known regarding its regulation, site of action or impact on chromatin architecture. In this proposal, we use genetic, molecular and biochemical methodologies to exploit Chl1 in the budding yeast model system to address fundamental questions of conserved pathways relevant to both birth defects and aneuploidy in humans. Specifically, we propose to elucidate the mechanism through which Chl1 is recruited to DNA specifically during DNA replication (Specific Aim1) and identify the mechanism through which Chl1 promotes cohesin deposition activity, focusing on chromatin architecture (Specific Aim 2)
Cornelia de Lange Syndrome (CdLS), Roberts Syndrome/SC-Phocomelia (RBS) and Warsaw Breakage Syndrome (WABS) are all developmental disorders involving cognitive function and birth defects. Mutations in genes that give rise to CdLS, RBS and WABS are the same genes that, when mutated, produce cell aneuploidy - a hallmark of cancer cells. This proposal uses genetic and biochemical methods to exploit recent findings that mutations in DNA helicase Chl1 (WABS) regulates those gene products that give rise to CdLS, produce birth defects akin to RBS, and pursue the molecular basis through which these and other development abnormalities are linked.
|Skibbens, Robert V (2015) Cell biology: cohesin rings leave loose ends. Curr Biol 25:R108-10|
|Tong, Kevin; Skibbens, Robert V (2015) Pds5 regulators segregate cohesion and condensation pathways in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 112:7021-6|
|Skibbens, Robert V (2011) Sticking a fork in cohesin--it's not done yet! Trends Genet 27:499-506|