The non-telomeric evolutionary trajectory of TRF2 in zebrafish reveals its specific roles in neurodevelopment and aging

Author:

Ying Yilin123,Hu Xuefei13,Han Peng13,Mendez-Bermudez Aaron12,Bauwens Serge2,Eid Rita2,Tan Li4,Pousse Mélanie2,Giraud-Panis Marie-Joseph2,Lu Yiming13,Gilson Eric125ORCID,Ye Jing13

Affiliation:

1. Department of Geriatrics, Medical center on Aging of Shanghai Ruijin Hospital, Shanghai Jiaotong University school of Medicine; International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital/CNRS/Inserm/Côte d’Azur University, PR China

2. Côte d’Azur University, CNRS, INSERM, IRCAN, Faculty of Medicine Nice, France

3. The State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherche en Sciences Du Vivant et Génomique, China

4. Shanghai Center for Plant Stress Center, CAS Center for Excellence in Molecular Plant Sciences, PR China

5. Department of Medical Genetics, CHU; Nice, FHU Oncoage, France

Abstract

Abstract The shelterin protein complex is required for telomere protection in various eukaryotic organisms. In mammals, the shelterin subunit TRF2 is specialized in preventing ATM activation at telomeres and chromosome end fusion in somatic cells. Here, we demonstrate that the zebrafish ortholog of TRF2 (encoded by the terfa gene) is protecting against unwanted ATM activation genome-wide. The terfa-compromised fish develop a prominent and specific embryonic neurodevelopmental failure. The heterozygous fish survive to adulthood but exhibit a premature aging phenotype. The recovery from embryonic neurodevelopmental failure requires both ATM inhibition and transcriptional complementation of neural genes. Furthermore, restoring the expression of TRF2 in glial cells rescues the embryonic neurodevelopment phenotype. These results indicate that the shelterin subunit TRF2 evolved in zebrafish as a general factor of genome maintenance and transcriptional regulation that is required for proper neurodevelopment and normal aging. These findings uncover how TRF2 links development to aging by separate functions in gene expression regulation and genome stability control.

Funder

National Natural Science Foundation of China

Program of Shanghai Academic/Technology Research Leader

Shanghai Municipal Education Commission

Fondation ARC

ANR

INCa

Inserm

French Government

Publisher

Oxford University Press (OUP)

Subject

Genetics

Reference41 articles.

1. Heterochromatin replication goes hand in hand with telomere protection;Mendez-Bermudez;Nat. Struct. Mol. Biol.,2020

2. How telomeres are replicated;Gilson;Nat. Rev. Mol. Cell Biol.,2007

3. Shelterin: the protein complex that shapes and safeguards human telomeres;de Lange;Genes Dev.,2005

4. One identity or more for telomeres?;Giraud-Panis;Front. Oncol.,2013

5. Telomeric localization of TRF2, a noval human telobox protein;Bilaud;Nat. Genet.,1997

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