Senescence induced by RECQL4 dysfunction contributes to Rothmund-Thomson syndrome features in mice

Huiming Lu, E. F. Fang, P. Sykora, T. Kulikowicz, Y. Zhang, K. G. Becker, D. L. Croteau, V. A. Bohr

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Cellular senescence refers to irreversible growth arrest of primary eukaryotic cells, a process thought to contribute to agingrelated degeneration and disease. Deficiency of RecQ helicase RECQL4 leads to Rothmund-Thomson syndrome (RTS), and we have investigated whether senescence is involved using cellular approaches and a mouse model. We first systematically investigated whether depletion of RECQL4 and the other four human RecQ helicases, BLM, WRN, RECQL1 and RECQL5, impacts the proliferative potential of human primary fibroblasts. BLM-, WRN- and RECQL4-depleted cells display increased staining of senescence-associated b-galactosidase (SA-b-gal), higher expression of p16INK4a or/and p21WAF1 and accumulated persistent DNA damage foci. These features were less frequent in RECQL1- and RECQL5-depleted cells. We have mapped the region in RECQL4 that prevents cellular senescence to its N-terminal region and helicase domain. We further investigated senescence features in an RTS mouse model, Recql4-deficient mice (Recql4HD). Tail fibroblasts from Recql4HD showed increased SA-b-gal staining and increased DNA damage foci. We also identified sparser tail hair and fewer blood cells in Recql4HD mice accompanied with increased senescence in tail hair follicles and in bone marrow cells. In conclusion, dysfunction of RECQL4 increases DNA damage and triggers premature senescence in both human and mouse cells, which may contribute to symptoms in RTS patients.

Original languageEnglish (US)
Article numbere1227
JournalCell Death and Disease
Volume5
Issue number5
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Rothmund-Thomson Syndrome
RecQ Helicases
Galactosidases
DNA Damage
Tail
Cell Aging
Fibroblasts
Staining and Labeling
Hair Follicle
Eukaryotic Cells
Bone Marrow Cells
Hair
Blood Cells
Growth

Keywords

  • Premature aging
  • RecQ helicase
  • RECQ4
  • RECQL4
  • Rothmund-Thomson syndrome
  • Senescence

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Lu, H., Fang, E. F., Sykora, P., Kulikowicz, T., Zhang, Y., Becker, K. G., ... Bohr, V. A. (2014). Senescence induced by RECQL4 dysfunction contributes to Rothmund-Thomson syndrome features in mice. Cell Death and Disease, 5(5), [e1227]. https://doi.org/10.1038/cddis.2014.168

Senescence induced by RECQL4 dysfunction contributes to Rothmund-Thomson syndrome features in mice. / Lu, Huiming; Fang, E. F.; Sykora, P.; Kulikowicz, T.; Zhang, Y.; Becker, K. G.; Croteau, D. L.; Bohr, V. A.

In: Cell Death and Disease, Vol. 5, No. 5, e1227, 01.01.2014.

Research output: Contribution to journalArticle

Lu, H, Fang, EF, Sykora, P, Kulikowicz, T, Zhang, Y, Becker, KG, Croteau, DL & Bohr, VA 2014, 'Senescence induced by RECQL4 dysfunction contributes to Rothmund-Thomson syndrome features in mice', Cell Death and Disease, vol. 5, no. 5, e1227. https://doi.org/10.1038/cddis.2014.168
Lu, Huiming ; Fang, E. F. ; Sykora, P. ; Kulikowicz, T. ; Zhang, Y. ; Becker, K. G. ; Croteau, D. L. ; Bohr, V. A. / Senescence induced by RECQL4 dysfunction contributes to Rothmund-Thomson syndrome features in mice. In: Cell Death and Disease. 2014 ; Vol. 5, No. 5.
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