STAG2-RAD21 complex: A unidirectional DNA ratchet mechanism in loop extrusion

Abstract

DNA loop extrusion plays a key role in the regulation of gene expression and the structural arrangement of chromatin. Most existing mechanistic models of loop extrusion depend on some type of ratchet mechanism, which should permit the elongation of loops while preventing their collapse, by enabling DNA to move in only one direction. STAG2 is already known to exert a role as DNA anchor, but the available structural data suggest a possible role in unidirectional DNA motion. In this work, a computational simulation framework was constructed to evaluate whether STAG2 could enforce such unidirectional displacement of a DNA double helix. The results reveal that STAG2 V-shape allows DNA sliding in one direction, but blocks opposite DNA movement via a linear ratchet mechanism. Furthermore, these results suggest that RAD21 binding to STAG2 controls its flexibility by narrowing the opening of its V-shape, which otherwise remains widely open in absence of RAD21. Therefore, in the proposed model, in addition to its already described role as a DNA anchor, the STAG2-RAD21 complex would be part of a ratchet mechanism capable of exerting directional selectivity on DNA sliding during loop extrusion. The identification of the molecular basis of the ratchet mechanism of loop extrusion is a critical step in unraveling new insights into a broad spectrum of chromatin activities and their implications for the mechanisms of chromatin-related diseases.