Hsp90 Is Essential for Chl1-Mediated Chromosome Segregation and Sister Chromatid Cohesion

Abstract

Recently, Hsp90 functional loss has been linked to aneuploidy; however, until now none of the components of sister chromatid cohesion (SCC) have been demonstrated as the putative clients of Hsp90. In this study, we have established that Chl1, the protein which is involved in maintaining sister chromatid cohesion as well as in preventing chromosome loss, is a direct client of Hsp90. Thus, with understanding of the molecular mechanism, how Hsp90 controls the cohesion machinery might reveal new insights which can be exploited further for attenuation of tumorigenesis.

Promotion of hyperthermic-induced rDNA hypercondensation inSaccharomyces cerevisiae

“…While there is a paucity of evidence that physically links Eco1 to Hsp82, it remains formally possible that Hsp82 promotes rDNA hypercondensation through Eco1 acetylation of cohesin subunits. In contrast to reports that Hsp82 promotes sister chromatid cohesion through stabilization of Chl1 DNA helicase (Khurana et al, 2018), which in turn promotes both Scc2 and cohesin binding to DNA (Skibbens, 2004; Rudra and Skibbens, 2012; Shen and Skibbens, 2017b; Mayer et al, 2004; Xu et al, 2007; Borges et al, 2013; Samora et al, 2016), we find no evidence in the current study that Chl1 (or changes in cohesin/condensin dynamics) adversely impacts rDNA hypercondensation. Future studies will be required to ascertain the extent to which, histone, cohesin and/or condensin modifications promote hyperthermic-induced rDNA hypercondensation in an Hsp90-dependent manner (Figure 7).…”

“…We validated GA-dependent Hsp90 inhibition on the Hsp90 client protein Chl1, a DNA helicase that promotes Scc2/cohesin deposition onto DNA (Supp. Figure 4; Skibbens, 2004; Khurana et al, 2018; Tahbaz et al, 2001). In combination, these results provide intriguing evidence that Hsp90 proteins may play ATP-independent ‘holding’ activities that are critical for rDNA responses to thermic stress.…”

“…Hsp90 family members exhibit receptor/kinase signal transduction activities and are well-established ATP-dependent foldases that promote protein maturation and thermic tolerance by ensuring proper folding of client proteins (Khurana et al, 2018; Morán Luengo et al, 2019; Genest et al, 2019). In addition, however, Hsp90 family members also exhibit ‘holdase’ functions independent of ATP binding/hydrolysis that include structural or scaffolding roles (Genest et al, 2019; Hoter et al, 2018; Csermely et al, 1998).…”

“…Here, we consider several possibilities regarding the mechanism through which HSP/C impact thermic-induced rDNA hypercondensation. Given the well-established role for HSP/C in stabilizing or refolding client proteins (Khurana et al, 2018; Morán Luengo et al, 2019; Genest et al, 2019), one plausible mode of action is through stabilization of an as yet undefined thermic-sensitive client protein required for rDNA hypercondensation. This client is unlikely to include cohesin or condensin, given that thermic stresses in HSP/C mutant cells result in increased rDNA axial loop lengths but not loss of either loop morphology (loops transitioning to puffs) or sister chromatid cohesion (one loop transitioning to two loops) (Shen and Skibbens, 2017a; Matos-Perdomo and Machín, 2018a).…”

Promotion of Hyperthermic-Induced rDNA Hypercondensation in Saccharomyces cerevisiae

“…Hsp90 family members exhibit receptor/kinase signal transduction activities and are well-established ATP-dependent foldases that promote protein maturation and thermic tolerance by ensuring proper folding of client proteins (Khurana et al 2018;Morán Luengo et al 2019;Genest et al 2019). In addition, however, Hsp90 family members also exhibit "holdase" functions independent of ATP binding/hydrolysis that include structural or scaffolding roles (Csermely et al 1998;Hoter et al 2018;Genest et al 2019).…”