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bioRxiv · 10.64898/2026.01.30.702899

ZCWPW1 organizes telomeric architecture to drive meiotic chromosome movements

Xie, W.·Gowder, M.·Bazzano, D.·Shami, A. N.·Pandey, A.·Frasca, M.·Paniker, L.·de Almeida, L. P.·Bharati, B. K.·Liang, J.·Toth, A.·DeSantis, M. E.·Nandakumar, J.·Nudler, E.·Mosalaganti, S.·Pezza, R.·Cole, F.·Hammoud, S.
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Abstract

Meiotic homolog pairing relies on programmed DNA recombination and large-scale chromosome movements, yet, how these genetic and mechanical events are coordinated remains unclear. ZCWPW1 is a histone reader that recognizes PRDM9-deposited chromatin marks. We identify an unexpected role for ZCWPW1 as a regulator of rapid prophase movements (RPMs). Using super-resolution imaging, we show that ZCWPW1 is strongly enriched at subtelomeric regions of mouse spermatocytes, where it stabilizes TRF1, LINC complex components, dynein, and meiosis-specific cohesin (STAG3). Loss of ZCWPW1 disrupts telomere architecture, weakens telomere-LINC- motor coupling, and abolishes chromosome movement, leading to defective synapsis and pairing, and persistence of DSBs. These defects are more severe than, and mechanistically independent of, those observed in Prdm9-/- spermatocytes. Together, our findings reveal that ZCWPW1 acts independently of PRDM9 as a chromatin-based intranuclear regulator of telomere architecture and telomere-led chromosome movements, thereby linking telomeric chromatin state to nuclear force transmission required for faithful meiotic progression. Significance StatementMeiotic pairing requires recombination and telomere-led chromosome movements, yet no chromatin factor has been shown to regulate both. We identify ZCWPW1 as the first chromatin-based regulator of rapid prophase movements. ZCWPW1 organizes telomeric chromatin and promotes cohesin and motor assembly at telomeres that for force transmission across the nuclear envelope. Loss of ZCWPW1 disrupts the telomere-nuclear envelope mechanical coupling, impairing motion and altering recombination. This function doesnt rely on PRDM9 despite their co-evolution and co-expression, challenging the prevailing view that ZCWPW1 only acts downstream of PRDM9 in DNA repair. Our findings show that chromatin readers can function as structural regulators of genome organization, revealing a conserved mechanism integrating chromosome structure, motion, and repair to ensure proper pairing and fertility.

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Xie, W., Gowder, M., Bazzano, D., Shami, A. N., Pandey, A., Frasca, M., Paniker, L., de Almeida, L. P., Bharati, B. K., Liang, J., Toth, A., DeSantis, M. E., Nandakumar, J., Nudler, E., Mosalaganti, S., Pezza, R., Cole, F., Hammoud, S.. 2026-02-02. ZCWPW1 organizes telomeric architecture to drive meiotic chromosome movements. https://doi.org/10.64898/2026.01.30.702899

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