Lack of DNA polymerase μ affects the kinetics of DNA double-strand break repair and impacts on cellular senescence

DNA Repair (Amst). 2010 Nov 10;9(11):1187-99. doi: 10.1016/j.dnarep.2010.09.001. Epub 2010 Oct 14.


The specialised DNA polymerase μ (pol μ) affects a sub-class of immunoglobulin genes rearrangements and haematopoietic development in vivo. These effects appear linked to double-strand breaks (DSBs) repair, but it is still unclear how and to what extent pol μ intervenes in this process. Using high-resolution quantitative imaging of DNA damage in irradiated wild-type and pol μ⁻(/)⁻ mouse embryonic fibroblasts (MEFs) we show that lack of pol μ results in delayed DSB repair kinetics and in persistent DNA damage. DNA damage triggers cellular senescence, and this response is thought to suppress cancer. Independent investigations either report or not a proliferative decline for MEFs lacking pol μ. Here we show pronounced senescence in pol μ⁻(/)⁻ MEFs, associated with high levels of the tumor-suppressor p16(INK4A) and the DNA damage response kinase CHK2. Importantly, cellular senescence is induced by culture stress and exacerbated by low doses of irradiation in pol μ⁻(/)⁻ MEFs. We also found that low doses of irradiation provoke delayed immortalisation in MEFs lacking pol μ. Pol μ⁻(/)⁻ MEFs thus exhibit a robust anti-proliferative defence in response to irreparable DNA damage. These findings indicate that sub-optimal DSB repair, due to the absence of an auxiliary DNA damage repair factor, can impact on cell fitness and thereby on cell fate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / radiation effects
  • Cell Line
  • Cell Proliferation / radiation effects
  • Cell Survival / radiation effects
  • Cellular Senescence* / radiation effects
  • DNA Breaks, Double-Stranded* / radiation effects
  • DNA Repair* / radiation effects
  • DNA-Directed DNA Polymerase / deficiency*
  • Dose-Response Relationship, Radiation
  • Kinetics
  • Mice


  • DNA polymerase mu
  • DNA-Directed DNA Polymerase