Zscan5b Deficiency Impairs DNA Damage Response and Causes Chromosomal Aberrations during Mitosis

Seiji Ogawa, Mitsutoshi Yamada, Akihiro Nakamura, Tohru Sugawara, Akari Nakamura, Shoko Miyajima, Yuichirou Harada, Reina Ooka, Ryuichiro Okawa, Jun Miyauchi, Hideki Tsumura, Yasunori Yoshimura, Kenji Miyado, Hidenori Akutsu, Mamoru Tanaka, Akihiro Umezawa, Toshio Hamatani

Research output: Contribution to journalArticle

Abstract

Zygotic genome activation (ZGA) begins after fertilization and is essential for establishing pluripotency and genome stability. However, it is unclear how ZGA genes prevent mitotic errors. Here we show that knockout of the ZGA gene Zscan5b, which encodes a SCAN domain with C2H2 zinc fingers, causes a high incidence of chromosomal abnormalities in embryonic stem cells (ESCs), and leads to the development of early-stage cancers. After irradiation, Zscan5b-deficient ESCs displayed significantly increased levels of γ-H2AX despite increased expression of the DNA repair genes Rad51l3 and Bard. Re-expression of Zscan5b reduced γ-H2AX content, implying a role for Zscan5b in DNA damage repair processes. A co-immunoprecipitation analysis showed that Zscan5b bound to the linker histone H1, suggesting that Zscan5b may protect chromosomal architecture. Our report demonstrates that the ZGA gene Zscan5b is involved in genomic integrity and acts to promote DNA damage repair and regulate chromatin dynamics during mitosis. In this article, Yamada and colleagues show that Zscan5b deficiency increases DNA stress, compromises chromosomal structure during mitosis, and leads to the development of early-stage cancers. Zscan5b deficiency may offer a murine model of human chromosomal breakage syndromes.

Original languageEnglish
Pages (from-to)1366-1379
Number of pages14
JournalStem cell reports
Volume12
Issue number6
DOIs
Publication statusPublished - 2019 Jun 11

Fingerprint

Aberrations
Mitosis
Chromosome Aberrations
DNA Damage
Genes
DNA Repair
Genome
Transcriptional Activation
DNA
Embryonic Stem Cells
Chemical activation
Chromosome Breakage
Genomic Instability
Repair
Immunoprecipitation
Fertilization
Histones
Chromatin
Stem cells
Neoplasms

Keywords

  • chromosome instability syndrome
  • embryonic stem cell
  • genome integrity
  • knockout mouse
  • mitosis
  • mosaicism
  • postreplicative DNA damage repair
  • Zscan5b

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Zscan5b Deficiency Impairs DNA Damage Response and Causes Chromosomal Aberrations during Mitosis. / Ogawa, Seiji; Yamada, Mitsutoshi; Nakamura, Akihiro; Sugawara, Tohru; Nakamura, Akari; Miyajima, Shoko; Harada, Yuichirou; Ooka, Reina; Okawa, Ryuichiro; Miyauchi, Jun; Tsumura, Hideki; Yoshimura, Yasunori; Miyado, Kenji; Akutsu, Hidenori; Tanaka, Mamoru; Umezawa, Akihiro; Hamatani, Toshio.

In: Stem cell reports, Vol. 12, No. 6, 11.06.2019, p. 1366-1379.

Research output: Contribution to journalArticle

Ogawa, S, Yamada, M, Nakamura, A, Sugawara, T, Nakamura, A, Miyajima, S, Harada, Y, Ooka, R, Okawa, R, Miyauchi, J, Tsumura, H, Yoshimura, Y, Miyado, K, Akutsu, H, Tanaka, M, Umezawa, A & Hamatani, T 2019, 'Zscan5b Deficiency Impairs DNA Damage Response and Causes Chromosomal Aberrations during Mitosis', Stem cell reports, vol. 12, no. 6, pp. 1366-1379. https://doi.org/10.1016/j.stemcr.2019.05.002
Ogawa, Seiji ; Yamada, Mitsutoshi ; Nakamura, Akihiro ; Sugawara, Tohru ; Nakamura, Akari ; Miyajima, Shoko ; Harada, Yuichirou ; Ooka, Reina ; Okawa, Ryuichiro ; Miyauchi, Jun ; Tsumura, Hideki ; Yoshimura, Yasunori ; Miyado, Kenji ; Akutsu, Hidenori ; Tanaka, Mamoru ; Umezawa, Akihiro ; Hamatani, Toshio. / Zscan5b Deficiency Impairs DNA Damage Response and Causes Chromosomal Aberrations during Mitosis. In: Stem cell reports. 2019 ; Vol. 12, No. 6. pp. 1366-1379.
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