- Title
- GCNA interacts with spartan and topoisomerase II to regulate genome stability
- Creator
- Dokshin, Gregoriy; Davis, Gregory; Sawle, Ashley; Eldridge, Matthew; Nicholls, Peter; Gourley, Taylin; Romer, Katherine; Molesworth, Luke; Tatnell, Hannah; Ozturk, Ahmet; de Rooij, Dirk; Hannon, Gregory; Page, David; Mello, Craig; Carmell, Michelle
- Date
- 2020
- Type
- Text; Journal article
- Identifier
- http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/174371
- Identifier
- vital:14816
- Identifier
-
https://doi.org/10.1016/j.devcel.2019.11.006
- Identifier
- ISBN:1534-5807 (ISSN)
- Abstract
- GCNA proteins are expressed across eukarya in pluripotent cells and have conserved functions in fertility. GCNA homologs Spartan (DVC-1) and Wss1 resolve DNA-protein crosslinks (DPCs), including Topoisomerase-DNA adducts, during DNA replication. Here, we show that GCNA mutants in mouse and C. elegans display defects in genome maintenance including DNA damage, aberrant chromosome condensation, and crossover defects in mouse spermatocytes and spontaneous genomic rearrangements in C. elegans. We show that GCNA and topoisomerase II (TOP2) physically interact in both mice and worms and colocalize on condensed chromosomes during mitosis in C. elegans embryos. Moreover, C. elegans gcna-1 mutants are hypersensitive to TOP2 poison. Together, our findings support a model in which GCNA provides genome maintenance functions in the germline and may do so, in part, by promoting the resolution of TOP2 DPCs. DNA topoisomerases help unwind DNA but occasionally get trapped, resulting in DNA-protein crosslinks (DPCs). DPCs damage DNA and threaten genomic integrity. Dokshin et al. find that GCNA protein family complements standard DPC processing machinery in resolving topoisomerase II DPCs to ensure heritable genome stability and germline immortality. © 2019 Elsevier Inc.; We thank S. Cheloufi, D. Bellott, D. Durning, L. Okumura, L. Teitz, and members of the Page and Mello labs for advice and discussion. We thank E. Spooner for mass spectrometry and K. Igarashi for technical assistance. We thank P. Boag and R. Pocock for access to microscopes and technical advice. Some strains provided by the CGC were supported by NIH ( P40 OD010440 ) and the International C. elegans Gene Knockout Consortium . This work was supported by the Life Sciences Research Foundation to M.A.C.; American Cancer Society 129916-PF16-232-RMC to G.A.D.; and NIH grants (R37 GM058800 and P01 HD078253 ) to C.C.M. G.J.H. is supported by Cancer Research UK and by a Royal Society Wolfson Research Professorship. D.C.P. and C.C.M. are Howard Hughes Medical Institute Investigators.
- Publisher
- Cell Press
- Relation
- Developmental Cell Vol. 52, no. 1 (2020), p. 53-68.e6
- Rights
- Metadata is freely available under a CCO license
- Rights
- Copyright © 2019 Elsevier Inc.
- Subject
- 06 Biological Sciences; 11 Medical and Health Sciences; DNA-protein crosslink (DPC) repair; DVC-1; GCNA; germ cells; Spartan; SprT; Top1; Top2; topoisomerase
- Reviewed
- Funder
- We thank S. Cheloufi, D. Bellott, D. Durning, L. Okumura, L. Teitz, and members of the Page and Mello labs for advice and discussion. We thank E. Spooner for mass spectrometry and K. Igarashi for technical assistance. We thank P. Boag and R. Pocock for access to microscopes and technical advice. Some strains provided by the CGC were supported by NIH ( P40 OD010440 ) and the International C. elegans Gene Knockout Consortium . This work was supported by the Life Sciences Research Foundation to M.A.C.; American Cancer Society 129916-PF16-232-RMC to G.A.D.; and NIH grants (R37 GM058800 and P01 HD078253 ) to C.C.M. G.J.H. is supported by Cancer Research UK and by a Royal Society Wolfson Research Professorship. D.C.P. and C.C.M. are Howard Hughes Medical Institute Investigators.
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