Fig. 1.

Mechanisms of MSCI initiation. A DAPI counterstaining of a “3D slide,” i.e., a slide prepared such that the gross three-dimensional organization of chromatin is preserved [94]. The dashed circle indicates the XY body. Scale bar: 10 μm. The image is originally from Abe et al. 2020 [30]. B Model of phase separation of the sex chromosomes. Key proteins involved at each step of the process are shown. C Model of the MSCI checkpoint: the physical seclusion of DDR factors from autosomes to the XY body is a critical checkpoint in the progression of meiosis and the development of gametes. At the onset of MSCI, DDR factors (shown as red) are excluded from autosomes and sequestered to the sex chromosomes. The physical seclusion of DDR factors on/at the XY body, which may involve phase separation, is a critical step in the MSCI checkpoint in the mid-pachytene stage of meiotic prophase I. While the MSCI checkpoint ensures meiotic stage progression in normal meiosis, the abolishment of MSCI enables the ectopic retention of DDR signals on/at autosomes; in turn, this triggers complete meiotic arrest and cell death in response to the checkpoint. D Model for the initiation of MSCI. ATR and its activator, TOPBP1, are recruited to unsynapsed axes in an MDC1- and H2AX-Y142-independent manner, resulting in phosphorylation of H2AX (γH2AX) on axes (left). Then, γH2AX recruits MDC1, which facilitates the progressive recruitment of ATR and TOPBP1, resulting in γH2AX and MDC1 spreading throughout loops (right). E Model for ATM-dependent loop extrusion in the somatic DDR. DSBs trigger the recruitment of ATM, which phosphorylates H2AX. As loop extrusion progresses, DNA passes by ATM enzymes at sites of DSBs, facilitating the phosphorylation of histones across large tracts of DNA