UNIVERSITY OF GOTHENBURG

Shibuya Lab

Shibuya Lab

Research

Meiosis and mitosis

In order to faithfully transmit their genetic information to their progeny, eukaryotic species possess a specialized form of cell division called meiosis. During meiosis, the chromosome number is accurately halved through two successive rounds of cell division following a single round of DNA replication, and the result is haploid germ cells. The characteristic events during meiosis are the pairing/synapsis and recombination of homologous chromosomes in prophase I. These steps ensure the formation of bivalent chromosomes specific in meiosis. Misregulation of these processes results in various genetic disorders including aneuploidy, Down Syndrome, infertility, and azoospermia.

Our studies try to address the fundamental question of how pairing/synapsis and recombination of homologous chromosomes are regulated on the molecular level during mammalian meiosis using the mouse as our model system. We employ a combination of genetic, molecular, cytological, and biochemical approaches.


Telomere in meiosis

Telomeres are composed of repetitive DNA sequences, to which the shelterin complex constitutively binds to protect the terminal DNA. To achieve pairing/synapsis of homologous chromosomes, meiotic chromosomes move within the nucleus by attachment of the telomeres to the nuclear membrane. Recent studies have identified a multi-subunit DNA-binding complex, TERB1-TERB2-MAJIN, that binds to telomeric DNA in mammalian germ cells[1],[2],[3],[4]. TERB1-TERB2-MAJIN is responsible for the attachment of telomeres to the nuclear membrane and drives the subsequent chromosome movement along the membrane. We are interested in the molecular regulations directing TERB1-TERB2-MAJIN complex assembly[5] as well the identification of novel factors regulating telomere dynamics in germ cells.



Meiotic homologous recombination

The DNA double strand breaks (DSBs) are well recognized as a major driving force in cancer development and progression. Despite its potential threatening, DSBs are intentionally introduced genome-wide specifically in germ cells. Meiotic DSBs are needed to exchange DNA strand between homologous chromosomes, as an initial step of meiotic homologous recombination. The meiotic DSBs are repaired by the invasion of the single-stranded DNA into the homologous DNA catalyzed by the RAD51 and DMC1 recombinases. The strand invasion results in the formation of a joint molecule structure that is ultimately resolved into a crossover.

Recently, we have identified a novel protein termed Meiotic localizer of BRCA2 (MEILB2)[6], which binds to the meiotic DSBs and forms complex with RAD51 as well as its mediator protein BRCA2. BRCA2 is a potent tumor suppressor involved in DNA break repair in cancer cells, however, its meiotic functions has been largely elusive. We found that MEILB2 promotes the localization of BRCA2, RAD51, and DMC1 at meiotic DSBs and ensures the proper DSB repair in meiosis.


Reference

  • [1] Shibuya H, Hernández-Hernández A, Morimoto A, Lumi Negishi, Höög C, Watanabe Y.
    MAJIN links telomeric DNA to the nuclear membrane by exchanging telomere cap.
    Cell. 2015
  • [2] Shibuya H, Morimoto A, Watanabe Y.
    The Dissection of Meiotic Chromosome Movement in Mice Using an In Vivo Electroporation Technique.
    Plos Genetics. 2014
  • [3] Shibuya H, Ishiguro K, Watanabe Y.
    The TRF1-binding protein TERB1 promotes chromosome movement and telomere rigidity in meiosis.
    Nature Cell Biology. 2014
  • [4] Morimoto A*, Shibuya H*, Zhu X, Kim J, Ishiguro K, Han M, Watanabe Y (*Equal contributions).
    A conserved KASH domain protein associates with telomeres, SUN1, and dynactin during mammalian meiosis.
    The Journal of Cell Biology. 2012
  • [5] Zhang J, Tu Z, Watanabe Y, Shibuya H.
    Distinct TERB1 domains regulate different protein interactions for meiotic telomere movement.
    Cell Reports. 2017
  • [6] Zhang J *, Fujiwara Y *, Yamamoto S, Shibuya H. (*co-first authors)
    A meiosis-specific BRCA2 binding protein recruits recombinases to DNA double-strand breaks to ensure homologous recombination.
    Nature Communications. 2019
Copyright © Hiroki Shibuya
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