PAXIP1-PAGR1 directs cohesin recruitment during break-induced telomere repair

Abstract

Cohesin is a conserved multiprotein complex (SMC1, SMC3, RAD21, and either STAG1 or STAG2) that organizes three-dimensional genome architecture and regulates chromosome segregation, gene expression, and DNA damage repair (1-4). Following double-strand breaks (DSBs), cohesin is recruited to sites of DNA damage - a process considered essential for efficient homologous recombination (5-15). Yet how DSB signaling elicits cohesin recruitment and subsequent cohesion establishment remains poorly understood. Here we show that telomere replication stress activates de novo STAG2-cohesin loading, thereby promoting break-induced telomeric DNA repair. We demonstrate that this DNA break-elicited cohesin recruitment is strictly controlled by the BRCT domain-containing DNA damage recognition factor PAXIP1 and its functional partner PAGR1. Cryo-electron microscopy structure reveals that PAGR1, together with PAXIP1, physically binds to a composite interface formed by the STAG2-RAD21 cohesin subcomplex. Complementary mutational and biochemical analyses define the molecular basis of this interaction and establish its essential role in break-induced cohesion establishment. Furthermore, we show that PAXIP1-PAGR1-enacted STAG2-cohesin recruitment complements with the PML body-associated pathway in orchestrating break-induced alternative lengthening of telomeres (ALT). Concurrent depletion of PML together with PAXIP1, PAGR1 or STAG2 disrupts ALT-mediated telomere maintenance, leading to end-to-end chromosomal fusion and mitotic cell death. Collectively, these findings uncover a distinctive molecular mechanism through which DSB signaling directs de novo cohesion establishment, and highlight its critical importance in break-induced telomere repair.

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BibTeX RIS

BibTeX

@misc{hwang2026paxip1pagr1,
  title = {{PAXIP1-PAGR1 directs cohesin recruitment during break-induced telomere repair}},
  author = {S. Y. Hwang and X. Wu and X. Huang and F. LI and Z. Wang and E. Y. Yu and Y. Xu and Z. Zhang and I. Moon and S.-A. Kim and B. Yamrom and S. Yang and Y. Wang and Y. Kwon and N. Lue and J. Paik and C. Dong and H. Zheng},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.14.751543},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.14.751543v1},
  note = {CC BY-NC},
}

RIS

TY  - UNPB
TI  - PAXIP1-PAGR1 directs cohesin recruitment during break-induced telomere repair
AU  - S. Y. Hwang
AU  - X. Wu
AU  - X. Huang
AU  - F. LI
AU  - Z. Wang
AU  - E. Y. Yu
AU  - Y. Xu
AU  - Z. Zhang
AU  - I. Moon
AU  - S.-A. Kim
AU  - B. Yamrom
AU  - S. Yang
AU  - Y. Wang
AU  - Y. Kwon
AU  - N. Lue
AU  - J. Paik
AU  - C. Dong
AU  - H. Zheng
PY  - 2026
DA  - 2026/09/14
PB  - bioRxiv
DO  - 10.64898/2026.09.14.751543
UR  - https://www.biorxiv.org/content/10.64898/2026.09.14.751543v1
AB  - Cohesin is a conserved multiprotein complex (SMC1, SMC3, RAD21, and either STAG1 or STAG2) that organizes three-dimensional genome architecture and regulates chromosome segregation, gene expression, and DNA damage repair (1-4). Following double-strand breaks (DSBs), cohesin is recruited to sites of DNA damage - a process considered essential for efficient homologous recombination (5-15). Yet how DSB signaling elicits cohesin recruitment and subsequent cohesion establishment remains poorly understood. Here we show that telomere replication stress activates de novo STAG2-cohesin loading, thereby promoting break-induced telomeric DNA repair. We demonstrate that this DNA break-elicited cohesin recruitment is strictly controlled by the BRCT domain-containing DNA damage recognition factor PAXIP1 and its functional partner PAGR1. Cryo-electron microscopy structure reveals that PAGR1, together with PAXIP1, physically binds to a composite interface formed by the STAG2-RAD21 cohesin subcomplex. Complementary mutational and biochemical analyses define the molecular basis of this interaction and establish its essential role in break-induced cohesion establishment. Furthermore, we show that PAXIP1-PAGR1-enacted STAG2-cohesin recruitment complements with the PML body-associated pathway in orchestrating break-induced alternative lengthening of telomeres (ALT). Concurrent depletion of PML together with PAXIP1, PAGR1 or STAG2 disrupts ALT-mediated telomere maintenance, leading to end-to-end chromosomal fusion and mitotic cell death. Collectively, these findings uncover a distinctive molecular mechanism through which DSB signaling directs de novo cohesion establishment, and highlight its critical importance in break-induced telomere repair.
ER  -

Abstract

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