Abstract
Non-homologous end joining (NHEJ) is one of the major DNA repair pathway in mammalian cell that can ligate a variety of DNA ends. However, how does all NHEJ factors communicate and organize together to achieve the final repair is still not clear. PAralog of XRCC4 and XLF (PAXX) was a new factor identified recently that play an important role in NHEJ. PAXX contributes to efficient NHEJ by interacting with Ku, which is a NHEJ key factor, and PAXX deficiency cause sensitivity to DNA double-strand break repair (DSBR). We observed that PAXX-deficient cells showed slight increase of homologous recombination (HR, which is another major DSBR repair pathways in mammalian cells). More importantly, we found that PAXX contributes to base excision repair pathway via interaction of polymerase beta (pol β). Temozolomide (TMZ) is one of the standard chemotherapies widely applied in glioblastoma. However, TMZ resistance and lack of potent chemotherapy agents can substitute TMZ. We observed that PAXX deficiency cause more sensitivity to TMZ-resistant glioma cells. In conclusion, the PAXX contributes to a variety of DNA repair pathways and TMZ resistance. Therefore, inhibition of PAXX may provide a promising way to overcome TMZ resistance and improve TMZ therapeutic effects in glioma treatment.
Highlights
DNA double-strand breaks (DSBs), which happened commonly in human cells, are extremely toxic and inevitable that one DSB can induce cell death (Rassool 2003; Scully and Xie 2005; Seluanov et al 2010)
Since these I-SceI sites are located in an invert order, the DSB generated by I-SceI are incompatible, which best mimic the natural DSB generated in cells (Fig. 1b)
We are interested in whether PAralog of X-ray repair cross-complementing 4 (XRCC4) and XLF (PAXX) participates in HR in glioma cells because HR can compete with Non-homologous end joining (NHEJ) for and is usually upregulated when NHEJ is impaired (Pierce et al 2001)
Summary
DNA double-strand breaks (DSBs), which happened commonly in human cells, are extremely toxic and inevitable that one DSB can induce cell death (Rassool 2003; Scully and Xie 2005; Seluanov et al 2010). Whereas NHEJ does not need template to join DSB (Kim et al 2005; Gerelchuluun et al 2015). Because NHEJ is free form the requirement of sister chromatid, this mechanism can be used in cells throughout the cell cycle (Aniukwu et al 2008; Bennardo et al 2008; Bartlett et al 2016). The NHEJ required factor includes Ku70/80 heterodimer (Ku), the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), the X-ray repair cross-complementing 4 (XRCC4)-ligase IV complex, and the XRCC4-like factor protein (XLF, as known as Cernunnos) (Gerelchuluun et al 2015). NHEJ is initiated with ring-shaped Ku binding that will recruit DNA-PKcs, XLF, and XRCC4/ligase IV.
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