R-loops (green), where DNA and RNA intertwine, are rare in a control cell (left) but prevalent in a cell deficient in BuGZ (right).
R-loops (green), where DNA and RNA intertwine, are rare in a control cell (left) but prevalent in a cell deficient in BuGZ (right).
Two mitotic proteins help control RNA splicing during interphase, show. The findings may offer an alternative explanation for how some drugs kill cancer cells.
Cancer drugs such as taxol halt mitosis. If cells remain in this paused state, DNA damage accumulates and p53 often gets switched on, triggering apoptosis. Researchers have assumed that the interruption in mitosis leads to DNA damage, which activates p53. However, whether taxol-induced tumor regression in vivo is due to mitotic arrest remains unclear. Some proteins that control mitosis also have nonmitotic roles, so cancer drugs could spur cell death by disrupting these alternative functions.
Wan et al. focused on two proteins, BuGZ and Bub3, that work together to ensure that chromosomes line up properly during mitosis. BuGZ helps deliver Bub3 to the kinetochores, where Bub3 joins the spindle assembly checkpoint that stops mitosis if chromosomes aren’t correctly connected to the spindle. Depleting BuGZ turned on p53 and caused cancer cells to commit suicide.
However, the researchers found BuGZ also bound to several proteins involved in RNA splicing. This process was perturbed when the researchers depleted BuGZ or Bub3 from control or cancer cells, causing DNA and RNA to intertwine and form so-called R-loops that promote DNA injury. If the researchers added an enzyme that removes R-loops, they could reduce the amounts of p53 activation and DNA damage in cells lacking BuGZ or Bub3. The study suggests that targeting the nonmitotic functions of mitotic proteins might offer a new way to turn on p53 and kill cancer cells.
