Kinesin Kif2C in regulation of DNA double strand break dynamics and repair

  1. Songli Zhu
  2. Mohammadjavad Paydar
  3. Feifei Wang
  4. Yanqiu Li
  5. Ling Wang
  6. Benoit Barrette
  7. Tadayoshi Bessho
  8. Benjamin H Kwok  Is a corresponding author
  9. Aimin Peng  Is a corresponding author
  1. University of Nebraska Medical Center, United States
  2. Université de Montréal, Canada

Abstract

DNA double strand breaks (DSBs) have detrimental effects on cell survival and genomic stability, and are related to cancer and other human diseases. In this study, we identified microtubule-depolymerizing kinesin Kif2C as a protein associated with DSB-mimicking DNA templates and known DSB repair proteins in Xenopus egg extracts and mammalian cells. The recruitment of Kif2C to DNA damage sites was dependent on both PARP and ATM activities. Kif2C knockdown or knockout led to accumulation of endogenous DNA damage, DNA damage hypersensitivity, and reduced DSB repair via both NHEJ and HR. Interestingly, Kif2C depletion, or inhibition of its microtubule depolymerase activity, reduced the mobility of DSBs, impaired the formation of DNA damage foci, and decreased the occurrence of foci fusion and resolution. Taken together, our study established Kif2C as a new player of the DNA damage response, and presented a new mechanism that governs DSB dynamics and repair.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Songli Zhu

    Department of Oral Biology, University of Nebraska Medical Center, Lincoln, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Mohammadjavad Paydar

    Département de médecine, Université de Montréal, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0569-7017
  3. Feifei Wang

    Department of Oral Biology, University of Nebraska Medical Center, Lincoln, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yanqiu Li

    Department of Oral Biology, University of Nebraska Medical Center, Lincoln, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ling Wang

    Department of Oral Biology, University of Nebraska Medical Center, Lincoln, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Benoit Barrette

    Département de médecine, Université de Montréal, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Tadayoshi Bessho

    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Lincoln, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8719-9646
  8. Benjamin H Kwok

    Département de médecine, Université de Montréal, Montréal, Canada
    For correspondence
    benjamin.kwok@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
  9. Aimin Peng

    Department of Oral Biology, University of Nebraska Medical Center, Lincoln, United States
    For correspondence
    aimin.peng@unmc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2452-1949

Funding

National Institutes of Health (CA172574)

  • Aimin Peng

Canadian Institutes of Health Research (148982)

  • Benjamin H Kwok

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Wolf-Dietrich Heyer, University of California, Davis, United States

Publication history

  1. Received: November 7, 2019
  2. Accepted: January 16, 2020
  3. Accepted Manuscript published: January 17, 2020 (version 1)
  4. Accepted Manuscript updated: January 21, 2020 (version 2)
  5. Version of Record published: February 11, 2020 (version 3)

Copyright

© 2020, Zhu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,211
    Page views
  • 480
    Downloads
  • 18
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Songli Zhu
  2. Mohammadjavad Paydar
  3. Feifei Wang
  4. Yanqiu Li
  5. Ling Wang
  6. Benoit Barrette
  7. Tadayoshi Bessho
  8. Benjamin H Kwok
  9. Aimin Peng
(2020)
Kinesin Kif2C in regulation of DNA double strand break dynamics and repair
eLife 9:e53402.
https://doi.org/10.7554/eLife.53402

Further reading

    1. Cell Biology
    2. Neuroscience
    Lauritz Kennedy et al.
    Research Article

    Neonatal cerebral hypoxia-ischemia (HI) is the leading cause of death and disability in newborns with the only current treatment being hypothermia. An increased understanding of the pathways that facilitate tissue repair after HI may aid the development of better treatments. Here, we study the role of lactate receptor HCAR1 in tissue repair after neonatal HI in mice. We show that HCAR1 knockout mice have reduced tissue regeneration compared with wildtype mice. Furthermore, proliferation of neural progenitor cells and glial cells, as well as microglial activation was impaired. Transcriptome analysis showed a strong transcriptional response to HI in the subventricular zone of wildtype mice involving about 7300 genes. In contrast, the HCAR1 knockout mice showed a modest response, involving about 750 genes. Notably, fundamental processes in tissue repair such as cell cycle and innate immunity were dysregulated in HCAR1 knockout. Our data suggest that HCAR1 is a key transcriptional regulator of pathways that promote tissue regeneration after HI.

    1. Cell Biology
    2. Developmental Biology
    Swathy Babu et al.
    Research Article

    Btg3-associated nuclear protein (Banp) was originally identified as a nuclear matrix-associated region (MAR)-binding protein and it functions as a tumor suppressor. At the molecular level, Banp regulates transcription of metabolic genes via a CGCG-containing motif called the Banp motif. However, its physiological roles in embryonic development are unknown. Here, we report that Banp is indispensable for the DNA damage response and chromosome segregation during mitosis. Zebrafish banp mutants show mitotic cell accumulation and apoptosis in developing retina. We found that DNA replication stress and tp53-dependent DNA damage responses were activated to induce apoptosis in banp mutants, suggesting that Banp is required for regulation of DNA replication and DNA damage repair. Furthermore, consistent with mitotic cell accumulation, chromosome segregation was not smoothly processed from prometaphase to anaphase in banp morphants, leading to a prolonged M-phase. Our RNA- and ATAC-sequencing identified 31 candidates for direct Banp target genes that carry the Banp motif. Interestingly, a DNA replication fork regulator, wrnip1, and two chromosome segregation regulators, cenpt and ncapg, are included in this list. Thus, Banp directly regulates transcription of wrnip1 for recovery from DNA replication stress, and cenpt and ncapg for chromosome segregation during mitosis. Our findings provide the first in vivo evidence that Banp is required for cell-cycle progression and cell survival by regulating DNA damage responses and chromosome segregation during mitosis.