PDS5A and TOP2B cooperate for chromatin recruitment via CTCF

Abstract PDS5A, a regulatory subunit of the cohesin complex, and topoisomerase IIB (TOP2B), an enzyme resolving DNA topological problems, interact with CTCF and regulate transcription, chromatin loops, and genome organization. Yet, how PDS5A and TOP2B are recruited to chromatin to exert their function is not well-understood. Here, we studied the functional relationship between PDS5A and TOP2B and the resultant impact on genome organization and gene expression. Interestingly, TOP2B-PDS5A cooperate for their recruitment to CTCF-bound chromatin sites. The presence of catalytically active TOP2B increased PDS5A occupancy genome-wide. Notably, a novel PDS5A-CTCF interaction region in the CTCF N-terminal 95-116aa was required for CTCF-PDS5A-TOP2B interaction in vitro as well as for active TOP2B-mediated enrichment of PDS5A chromatin occupancy in vivo. The loss of CTCF(95-116aa) led to a reduced number of chromatin loops and dysregulated gene expression. In gliomas, PDS5A and TOP2B expression levels are variable and correlated, contributing to apparent heterogeneity in gene expression. Indeed, inducible knockdown of PDS5A led to reduced TOP2B occupancy and altered gene expression in the glioma genome. Importantly, PDS5A mediated sensitivity to TOP2 cancer drugs in glioma cells. This newly recognized functional interaction between PDS5A and TOP2B at chromatin boundaries clarifies the mechanisms fostering gene regulation through genome organization, with implications for glioma therapeutics. Competing Interest Statement D.R. was a cofounder of Constellation Pharmaceuticals and Fulcrum Therapeutics. Currently, D.R. has no affiliation with either company. The authors declare that they have no other competing interests.