The TERB1 MYB domain suppresses telomere erosion in meiotic prophase I.

Kexin Zhang,Cassandra Zuckerman,Hiroki Shibuya,Agata Tarczykowska,Jayakrishnan Nandakumar,Devon F Pendlebury,Deepesh Kumar Gupta

doi:10.1016/j.celrep.2021.110289

Kexin Zhang, Cassandra Zuckerman + Show 5 more

Open Access

https://doi.org/10.1016/j.celrep.2021.110289

Copy DOI

Abstract

SUMMARYThe meiosis-specific telomere-binding protein TERB1 anchors telomeres to the nuclear envelope and drives chromosome movements for the pairing of homologous chromosomes. TERB1 has an MYB-like DNA-binding (MYB) domain, which is a hallmark of telomeric DNA-binding proteins. Here, we demonstrate that the TERB1 MYB domain has lost its canonical DNA-binding activity. The analysis of Terb1 point mutant mice expressing TERB1 lacking its MYB domain showed that the MYB domain is dispensable for telomere localization of TERB1 and the downstream TERB2-MAJIN complex, the promotion of homologous pairing, and even fertility. Instead, the TERB1 MYB domain regulates the enrichment of cohesin and promotes the remodeling of axial elements in the early-to-late pachytene transition, which suppresses telomere erosion. Considering its conservation across metazoan phyla, the TERB1 MYB domain is likely to be important for the maintenance of telomeric DNA and thus for genomic integrity by suppressing meiotic telomere erosion over long evolutionary timescales.

Highlights

Telomeres, which are found at the ends of linear eukaryotic chromosomes, are composed of G-rich repeat DNA sequences— (TTAGGG)n in vertebrates
Proteins that bind to telomeric double-strand DNA typically have a single MYB-like DNA-binding (MYB) domain at their C terminus that directly recognizes the telomeric dsDNA in a sequence-specific manner, such as Taz1 in fission yeast, RTBP1 in rice, and TRF1/2 in mammals (Broccoli et al, 1997; Spink et al, 2000; Yu et al, 2000)
Because the single substitution of arginine 425 to valine in human TRF1 is sufficient to abrogate the dsDNA-binding activity (Fairall et al, 2001), we hypothesized that the dsDNA-binding activity was lost in the TERB1 MYB domain

Summary

Introduction

Telomeres, which are found at the ends of linear eukaryotic chromosomes, are composed of G-rich repeat DNA sequences— (TTAGGG)n in vertebrates. The recognition of telomeric dsDNA via these MYB domain proteins leads to the assemblies of downstream telomere-associating proteins, forming the so-called shelterin complex, which ensures the fundamental telomeric functions, such as chromosome end protection and telomere length maintenance (de Lange, 2010). In addition to these housekeeping functions, telomeres have an evolutionarily conserved role during meiosis. TERB1 binds to the shelterin protein TRF1 through its TRF1-binding (TRFB) domain, which localizes TERB1 to telomeres, where it recruits the downstream transmembrane components TERB2-MAJIN and SUN1-KASH5 for telomere attachment and movement, respectively. Recent studies have identified pathological mutations in TERB1, TERB2, and MAJIN in human non-obstructive azoospermia patients, corroborating these genes’ critical roles in human reproduction (Alhathal et al, 2020; Riera-Escamilla et al, 2020; Salas-Huetos et al, 2021)

Methods

Results

Discussion

Conclusion