TY - JOUR
T1 - GCNA Preserves Genome Integrity and Fertility Across Species
AU - Bhargava, Varsha
AU - Goldstein, Courtney D.
AU - Russell, Logan
AU - Xu, Lin
AU - Ahmed, Murtaza
AU - Li, Wei
AU - Casey, Amanda
AU - Servage, Kelly
AU - Kollipara, Rahul
AU - Picciarelli, Zachary
AU - Kittler, Ralf
AU - Yatsenko, Alexander
AU - Carmell, Michelle
AU - Orth, Kim
AU - Amatruda, James F.
AU - Yanowitz, Judith L.
AU - Buszczak, Michael
N1 - Funding Information:
We would like to thank K. McKim, T. Orr-Weaver, D. Ardnt-Jovin, M. Osterfield, K. Dubrovinski, M. Lilly, J. Abrams, H. Richardson, the Bloomington Drosophila Stock Center, and the Developmental Studies Hybridoma Bank for Drosophila reagents, and S. Smolikove and A. Jaramillo-Lambert for worm antibodies. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs, United States ( P40 OD010440 ). We also thank D. Jangam and E. Bertran for their help with RNA sequencing data analysis. We thank members of the Buszczak and Yanowitz labs for comments and advice and Jose Cabrera for help in preparing the graphical abstract. V.B. was supported by HHMI (grant no. 56006776 ), NIGMS ( T32GM10977601 ), and a fellowship from the Center for Regenerative Science and Medicine at UT Southwestern. C.D.G. was supported by NIGMS ( 5T32GM008203-30 ). This work was also supported in various phases by awards from NIGMS ( R01GM086647 and R01GM125812 ), NIA ( R01AG047318 ), and the Simmons Comprehensive Cancer Center to M.B.; NIGMS ( R01GM104007 ) to J.L.Y; and NIGMS ( R01GM127569 ) to J.L.Y. and M.B. J.F.A. was supported by grant RP110394 from the Cancer Prevention and Research Institute of Texas and a Consortium Research Grant from the St. Baldrick's Foundation . The EM core at UT Southwestern is supported by NIH S10 OD020103-01 .
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2020/1/6
Y1 - 2020/1/6
N2 - The propagation of species depends on the ability of germ cells to protect their genome from numerous exogenous and endogenous threats. While these cells employ ubiquitous repair pathways, specialized mechanisms that ensure high-fidelity replication, chromosome segregation, and repair of germ cell genomes remain incompletely understood. We identified Germ Cell Nuclear Acidic Peptidase (GCNA) as a conserved regulator of genome stability in flies, worms, zebrafish, and human germ cell tumors. GCNA contains an acidic intrinsically disordered region (IDR) and a protease-like SprT domain. In addition to chromosomal instability and replication stress, Gcna mutants accumulate DNA-protein crosslinks (DPCs). GCNA acts in parallel with the SprT domain protein Spartan. Structural analysis reveals that while the SprT domain is needed to limit DNA damage, the IDR imparts significant function. This work shows that GCNA protects germ cells from various sources of damage, providing insights into conserved mechanisms that promote genome integrity across generations.
AB - The propagation of species depends on the ability of germ cells to protect their genome from numerous exogenous and endogenous threats. While these cells employ ubiquitous repair pathways, specialized mechanisms that ensure high-fidelity replication, chromosome segregation, and repair of germ cell genomes remain incompletely understood. We identified Germ Cell Nuclear Acidic Peptidase (GCNA) as a conserved regulator of genome stability in flies, worms, zebrafish, and human germ cell tumors. GCNA contains an acidic intrinsically disordered region (IDR) and a protease-like SprT domain. In addition to chromosomal instability and replication stress, Gcna mutants accumulate DNA-protein crosslinks (DPCs). GCNA acts in parallel with the SprT domain protein Spartan. Structural analysis reveals that while the SprT domain is needed to limit DNA damage, the IDR imparts significant function. This work shows that GCNA protects germ cells from various sources of damage, providing insights into conserved mechanisms that promote genome integrity across generations.
KW - ACRC
KW - DNA repair
KW - DNA-protein crosslink
KW - SprT domain
KW - acidic repeat containing
KW - chromosome instability
KW - chromosome segregation
KW - germ cell
KW - intrinsically disordered region
KW - transgenerational inheritance
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U2 - 10.1016/j.devcel.2019.11.007
DO - 10.1016/j.devcel.2019.11.007
M3 - Article
C2 - 31839537
AN - SCOPUS:85077065598
SN - 1534-5807
VL - 52
SP - 38-52.e10
JO - Developmental cell
JF - Developmental cell
IS - 1
ER -