Aberrant Activation of Chromosome Asynapsis Checkpoint Triggers Oocyte Elimination

Overview

Journal Nat Commun

Specialty Biology

Date 2025 Mar 6

PMID 40050306

Authors

Xiaofei Jiao

Zhongyang Liang

Jiwei Li

Long Bai

Jun Xu

Yidan Liu

Lin-Yu Lu

Affiliations

Soon will be listed here.

Abstract

Chromosome synapsis is an evolutionarily conserved process essential for meiotic recombination. HORMAD1 and HORMAD2, which monitor chromosome asynapsis by localizing to unsynapsed chromosome axes, are removed from synapsed chromosome axes by TRIP13, though the biological significance of this process remains unclear. We show that when HORMAD1 and HORMAD2 are retained on synapsed chromosome axes, they recruit BRCA1, activate chromosome asynapsis checkpoint, and trigger oocyte elimination. Unexpectedly, N-terminal tagging retains HORMAD1 and HORMAD2 on synapsed chromosome axes without triggering oocyte elimination due to defective BRCA1 recruitment. Mechanistically, HORMAD1 co-immunoprecipitates with BRCA1 readily, not through the canonical closure motif-binding mode but via an interface on its HORMA domain near the N-terminus. HORMAD2 co-immunoprecipitates with BRCA1 weakly but also regulates its recruitment. Collectively, the TRIP13-dependent removal of HORMAD1 and HORMAD2 from synapsed chromosome axes is essential for female fertility, preventing aberrant chromosome asynapsis checkpoint activation and unintended oocyte elimination.

References

Daniel K, Lange J, Hached K, Fu J, Anastassiadis K, Roig I . Meiotic homologue alignment and its quality surveillance are controlled by mouse HORMAD1. Nat Cell Biol. 2011; 13(5):599-610. PMC: 3087846. DOI: 10.1038/ncb2213. View

Qiao H, Rao H, Yun Y, Sandhu S, Fong J, Sapre M . Impeding DNA Break Repair Enables Oocyte Quality Control. Mol Cell. 2018; 72(2):211-221.e3. PMC: 6426715. DOI: 10.1016/j.molcel.2018.08.031. View

Li X, Li X, Schimenti J . Mouse pachytene checkpoint 2 (trip13) is required for completing meiotic recombination but not synapsis. PLoS Genet. 2007; 3(8):e130. PMC: 1941754. DOI: 10.1371/journal.pgen.0030130. View

Ravindranathan R, Raveendran K, Papanikos F, San-Segundo P, Toth A . Chromosomal synapsis defects can trigger oocyte apoptosis without elevating numbers of persistent DNA breaks above wild-type levels. Nucleic Acids Res. 2022; 50(10):5617-5634. PMC: 9177993. DOI: 10.1093/nar/gkac355. View

Zickler D, Kleckner N . Recombination, Pairing, and Synapsis of Homologs during Meiosis. Cold Spring Harb Perspect Biol. 2015; 7(6). PMC: 4448610. DOI: 10.1101/cshperspect.a016626. View

Wojtasz L, Daniel K, Roig I, Bolcun-Filas E, Xu H, Boonsanay V . Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase. PLoS Genet. 2009; 5(10):e1000702. PMC: 2758600. DOI: 10.1371/journal.pgen.1000702. View

Matsuoka S, Huang M, Elledge S . Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science. 1998; 282(5395):1893-7. DOI: 10.1126/science.282.5395.1893. View

Liu K, Wang Y, Zhu Q, Li P, Chen J, Tang Z . Aberrantly expressed HORMAD1 disrupts nuclear localization of MCM8-MCM9 complex and compromises DNA mismatch repair in cancer cells. Cell Death Dis. 2020; 11(7):519. PMC: 7347845. DOI: 10.1038/s41419-020-2736-1. View

Elinati E, Zielinska A, McCarthy A, Kubikova N, Maciulyte V, Mahadevaiah S . The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes. Nat Commun. 2020; 11(1):2598. PMC: 7248069. DOI: 10.1038/s41467-020-16441-z. View

10.

Turner J . Meiotic Silencing in Mammals. Annu Rev Genet. 2015; 49:395-412. DOI: 10.1146/annurev-genet-112414-055145. View

11.

Pabla N, Huang S, Mi Q, Daniel R, Dong Z . ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. J Biol Chem. 2007; 283(10):6572-83. DOI: 10.1074/jbc.M707568200. View

12.

Shin Y, Choi Y, Erdin S, Yatsenko S, Kloc M, Yang F . Hormad1 mutation disrupts synaptonemal complex formation, recombination, and chromosome segregation in mammalian meiosis. PLoS Genet. 2010; 6(11):e1001190. PMC: 2973818. DOI: 10.1371/journal.pgen.1001190. View

13.

Fujiwara Y, Horisawa-Takada Y, Inoue E, Tani N, Shibuya H, Fujimura S . Meiotic cohesins mediate initial loading of HORMAD1 to the chromosomes and coordinate SC formation during meiotic prophase. PLoS Genet. 2020; 16(9):e1009048. PMC: 7518614. DOI: 10.1371/journal.pgen.1009048. View

14.

Kowalczykowski S . An Overview of the Molecular Mechanisms of Recombinational DNA Repair. Cold Spring Harb Perspect Biol. 2015; 7(11). PMC: 4632670. DOI: 10.1101/cshperspect.a016410. View

15.

Rinaldi V, Bolcun-Filas E, Kogo H, Kurahashi H, Schimenti J . The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure. Mol Cell. 2017; 67(6):1026-1036.e2. PMC: 5621520. DOI: 10.1016/j.molcel.2017.07.027. View

16.

Lin Z, Hsu P, Xing X, Fang J, Lu Z, Zou Q . Mettl3-/Mettl14-mediated mRNA N-methyladenosine modulates murine spermatogenesis. Cell Res. 2017; 27(10):1216-1230. PMC: 5630681. DOI: 10.1038/cr.2017.117. View

17.

Ye Q, Kim D, Dereli I, Rosenberg S, Hagemann G, Herzog F . The AAA+ ATPase TRIP13 remodels HORMA domains through N-terminal engagement and unfolding. EMBO J. 2017; 36(16):2419-2434. PMC: 5556265. DOI: 10.15252/embj.201797291. View

18.

Bai L, Li P, Xiang Y, Jiao X, Chen J, Song L . BRCA1 safeguards genome integrity by activating chromosome asynapsis checkpoint to eliminate recombination-defective oocytes. Proc Natl Acad Sci U S A. 2024; 121(19):e2401386121. PMC: 11087798. DOI: 10.1073/pnas.2401386121. View

19.

Di Giacomo M, Barchi M, Baudat F, Edelmann W, Keeney S, Jasin M . Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants. Proc Natl Acad Sci U S A. 2005; 102(3):737-42. PMC: 545532. DOI: 10.1073/pnas.0406212102. View

20.

Kogo H, Tsutsumi M, Ohye T, Inagaki H, Abe T, Kurahashi H . HORMAD1-dependent checkpoint/surveillance mechanism eliminates asynaptic oocytes. Genes Cells. 2012; 17(6):439-54. DOI: 10.1111/j.1365-2443.2012.01600.x. View