GCNA Interacts with Spartan and Topoisomerase II to Regulate Genome Stability

Gregoriy A Dokshin; Gregory M Davis; Ashley D Sawle; Matthew D Eldridge; Peter K Nicholls; Taylin E Gourley; Katherine A Romer; Luke W Molesworth; Hannah R Tatnell; Ahmet R Ozturk; Dirk G de Rooij; Gregory J Hannon; David C Page; Craig C Mello; Michelle A Carmell

doi:10.1016/j.devcel.2019.11.006

GCNA Interacts with Spartan and Topoisomerase II to Regulate Genome Stability

Dev Cell. 2020 Jan 6;52(1):53-68.e6. doi: 10.1016/j.devcel.2019.11.006. Epub 2019 Dec 12.

Authors

Affiliations

¹ RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
² School of Health and Life Sciences, Federation University, VIC 3841, Australia.
³ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
⁴ Whitehead Institute, 455 Main Street, Cambridge, MA 02142, USA.
⁵ Whitehead Institute, 455 Main Street, Cambridge, MA 02142, USA; Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁶ Whitehead Institute, 455 Main Street, Cambridge, MA 02142, USA; Reproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht 3584, the Netherlands; Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam 1105, the Netherlands.
⁷ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
⁸ Whitehead Institute, 455 Main Street, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142, USA.
⁹ RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: [email protected].
¹⁰ RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Whitehead Institute, 455 Main Street, Cambridge, MA 02142, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: [email protected].

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.

Keywords: DNA-protein crosslink (DPC) repair; DVC-1; GCNA; Spartan; SprT; Top1; Top2; germ cells; topoisomerase.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Caenorhabditis elegans
DNA Damage
DNA Repair
DNA Replication*
DNA Topoisomerases, Type II / genetics
DNA Topoisomerases, Type II / metabolism*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Genome
Genomic Instability*
Germ Cells
Male
Mice
Mice, Inbred C57BL
Mitosis*
Mutation
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Spermatocytes / cytology*
Spermatocytes / metabolism
Spermatogenesis

Substances

DNA-Binding Proteins
Nuclear Proteins
Spartan protein, mouse
DNA Topoisomerases, Type II

Abstract

Publication types

MeSH terms

Substances

Grants and funding