論文

査読有り 国際誌
2020年7月31日

SLFN11 promotes stalled fork degradation that underlies the phenotype in Fanconi anemia cells.

Blood
  • Yusuke Okamoto
  • Masako Abe
  • Anfeng Mu
  • Yasuko Tempaku
  • Colette B Rogers
  • Ayako L Mochizuki
  • Yoko Katsuki
  • Masato T Kanemaki
  • Akifumi Takaori-Kondo
  • Alexandra T Sobeck
  • Anja-Katrin Bielinsky
  • Minoru Takata
  • 全て表示

137
3
開始ページ
336
終了ページ
348
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1182/blood.2019003782

Fanconi anemia (FA) is a hereditary disorder caused by mutations in any one of 22 FA genes. The disease is characterized by hypersensitivity to interstrand crosslink (ICL) inducers such as mitomycin C (MMC). In addition to promoting ICL repair, FA proteins such as RAD51, BRCA2, or FANCD2 protect stalled replication forks from nucleolytic degradation during replication stress, which may have a profound impact on FA pathophysiology. Recent studies showed that expression of the putative DNA/RNA helicase SLFN11 in cancer cells correlates with cell death upon chemotherapeutic treatment. However, the underlying mechanisms of SLFN11-mediated DNA damage sensitivity remain unclear. Since SLFN11 expression is high in hematopoietic stem cells, we hypothesized that SLFN11 depletion might ameliorate the phenotypes of FA cells. Here we report that SLFN11 knockdown in the FA patient-derived FANCD2-deficient PD20 cell line improved cell survival upon treatment with ICL inducers. FANCD2-/-SLFN11-/- HAP1 cells also displayed phenotypic rescue, including reduced levels of MMC-induced chromosome breakage compared to FANCD2-/- cells. Importantly, we found that SLFN11 promotes extensive fork degradation in FANCD2-/- cells. The degradation process is mediated by the nucleases MRE11 or DNA2 and depends on the SLFN11 ATPase activity. This observation was accompanied by an increased RAD51 binding at stalled forks, consistent with the role of RAD51 antagonizing nuclease recruitment and subsequent fork degradation. Suppression of SLFN11 protects nascent DNA tracts even in wild type cells. We conclude that SLFN11 destabilizes stalled replication forks, and this function may contribute to the attrition of hematopoietic stem cells in FA.

リンク情報
DOI
https://doi.org/10.1182/blood.2019003782
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32735670
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819757
ID情報
  • DOI : 10.1182/blood.2019003782
  • PubMed ID : 32735670
  • PubMed Central 記事ID : PMC7819757

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