MAJIN Links Telomeric DNA to the Nuclear Membrane by Exchanging Telomere Cap

Abstract

In meiosis, telomeres attach to the inner nuclear membrane (INM) and drive the chromosome movement required for homolog pairing and recombination. Here, we address the question of how telomeres are structurally adapted for the meiotic task. We identify a multi-subunit meiotic telomere-complex, TERB1/2-MAJIN, which takes over telomeric DNA from the shelterin complex in mouse germ cells. TERB1/2-MAJIN initially assembles on the INM sequestered by its putative transmembrane subunit MAJIN. In early meiosis, telomere attachment is achieved by the formation of a chimeric complex of TERB1/2-MAJIN and shelterin. The chimeric complex matures during prophase into DNA-bound TERB1/2-MAJIN by releasing shelterin, forming a direct link between telomeric DNA and the INM. These hierarchical processes, termed "telomere cap exchange," are regulated by CDK-dependent phosphorylation and the DNA-binding activity of MAJIN. Further, we uncover a positive feedback between telomere attachment and chromosome movement, revealing a comprehensive regulatory network underlying meiosis-specific telomere function in mammals.

Speedy A–Cdk2 binding mediates initial telomere–nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation

“…In recent years, several meiosis-specific structural units that mediate chromosome attachment on the telomeric end have been identified in mice, including SUN1, KASH5, TERB1/2, and MAJIN (4)(5)(6)8). Our present study suggests that Speedy A, which was previously known solely as a Cdk activator, has a structural function in the formation of the telomere complex during meiotic prophase I in mammals.…”

“…We further analyzed the telomeric cap exchange that takes place in pachytene-stage germ cells (5). In wild-type spermatocytes, we observed that TRF2 (telomeric repeat-binding factor 2), a shelterin protein (28,29), was disassociated from the end of the chromosome axis and formed a ring structure, indicating that cap exchange had occurred (Fig.…”

“…In recent years, several meiosis-specific structural molecules that mediate telomere-NE attachment have been identified in mice, such as TERB1 (telomere repeat binding bouquet formation protein 1), SUN1 (Sad1 and UNC84 domain containing 1), KASH5 (Klarsicht/ANC-1/Syne/homology 5), TERB2 (telomere repeat binding bouquet formation protein 2), and MAJIN (membraneanchored junction protein), and mice lacking any one of SUN1, KASH5, TERB1, TERB2, or MAJIN display impaired telomere attachment and are sterile (4)(5)(6)(7)(8). Moreover, cyclin-dependent kinase 2 (Cdk2) is localized to telomeres in mouse spermatocytes and prophase I oocytes (9), and loss of Cdk2 leads to sterility in both male and female mice (10,11).…”

The F-Box Protein ZYGO1 Mediates Bouquet Formation to Promote Homologous Pairing, Synapsis, and Recombination in Rice Meiosis

“…Factors affecting telomere bouquet formation mainly participate in two aspects of telomere behavior: telomere attachment to the INM and subsequent telomere movement along the INM. Many proteins have been identified that connect telomere proteins with INM proteins, such as Bouquet 1 (Bqt1), Bqt2, Bqt3, and Bqt4 in fission yeast (Schizosaccharomyces pombe) (Chikashige et al, 2006(Chikashige et al, , 2009, Nondisjunction 1 (Ndj1) in budding yeast (Saccharomyces cerevisiae) (Conrad et al, 1997;Trelles-Sticken et al, 2000), as well as Telomere repeat binding bouquet formation protein 1 (TERB1), TERB2, and membrane-anchored junction protein (MAJIN) in mouse (Mus musculus) (Shibuya et al, 2014(Shibuya et al, , 2015. These proteins tether telomeres to the INM to ensure bouquet formation.…”

Telomeric TERB1–TRF1 interaction is crucial for male meiosis

“…In addition to the LINC-complex protein SUN 1 (ref 1920–22 , MAJIN (membrane-anchored junction protein) 22 , CDK2 (cyclin-dependent kinases 2) 23 and Speedy/RINGO A (rapid inducer of G2/M progression in oocytes) 24 .…”