A novel Vps34 complex constrains loop extrusion-mediated P-H2A spreading

The establishment of appropriate phosphorylated histone H2AX ({gamma}H2AX) foci is required for the precise initiation of DNA damage response (DDR) signaling, which contributes to the efficient repair of DNA double-strand breaks (DSB)1. Therefore, it is important to understand exactly how {gamma}H2AX foci are established in response to DSB. Recently, an attractive mechanism has been proposed to explain this process2. DSB-anchored cohesin-mediated loop extrusion promotes H2AX-containing chromatin to pass through DSB-recruited ATM, by which H2AX is phosphorylated to form {gamma}H2AX foci on each side of the DSB. The loop extrusion-promoted enlargement of {gamma}H2AX-modified chromatin is halted upon cohesin encountering boundary factors such as CTCF. This cohesin-dependent mechanism was shown to be conserved among eukaryotic cells, because deletion of the cohesin regulator Pds5 in budding yeast also results in extended spreading of phosphorylated H2A at Ser129 (P-H2A)2. However, yeast lacks CTCF or CTCF-like boundary factors that restrict cohesion-mediated loop extrusion. Here, we report a novel vacuolar sorting protein 34 (Vps34) complex, which might function as a boundary factor that constrains cohesin-dependent loop extrusion-mediated P-H2A spreading.