15
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Common and Unique Genetic Interactions of the Poly(ADP-ribose) Polymerases PARP1 and PARP2 with DNA Double-Strand Break Repair Pathways

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          In mammalian cells, chromatin poly(ADP-ribos)ylation (PARylation) at sites of DNA Double-Strand Breaks (DSBs) is mediated by two highly related enzymes, PARP1 and PARP2. However, enzyme-specific genetic interactions with other DSB repair factors remain largely undefined. In this context, it was previously shown that mice lacking PARP1 and H2AX, a histone variant that promotes DSB repair throughout the cell cycle, or the core nonhomologous end-joining (NHEJ) factor Ku80 are not viable, while mice lacking PARP1 and the noncore NHEJ factor DNA-PKcs are severely growth retarded and markedly lymphoma-prone. Here, we have examined the requirement for PARP2 in these backgrounds. We find that, like PARP1, PARP2 is essential for viability in mice lacking H2AX. Moreover, treatment of H2AX-deficient primary fibroblasts or B lymphocytes with PARP inhibitors leads to activation of the G2/M checkpoint and accumulation of chromatid-type breaks in a lineage- and gene-dose dependent manner. In marked contrast to PARP1, loss of PARP2 does not result in additional phenotypes in growth, development or tumorigenesis in mice lacking either Ku80 or DNA-PKcs. Altogether these findings highlight specific nonoverlapping functions of PARP1 and PARP2 at H2AX-deficient chromatin during replicative phases of the cell cycle and uncover a unique requirement for PARP1 in NHEJ-deficient cells.

          Graphical abstract

          Related collections

          Author and article information

          Journal
          101139138
          30141
          DNA Repair (Amst)
          DNA Repair (Amst.)
          DNA repair
          1568-7864
          1568-7856
          29 July 2016
          16 June 2016
          September 2016
          01 September 2017
          : 45
          : 56-62
          Affiliations
          [a ]Department of Radiation Oncology and Molecular Radiation Sciences; Johns Hopkins School of Medicine, Baltimore, MD 21287, United States
          [b ]Biotechnology and Cell Signaling Unit, University of Strasbourg, 67412 Illkirch, France
          Author notes
          [* ] Corresponding author. Tel: +1 410 614 9224; fax: 410 502 2821. sfranco2@ 123456jhmi.edu (S.F.)
          Article
          PMC4979568 PMC4979568 4979568 nihpa800721
          10.1016/j.dnarep.2016.06.001
          4979568
          27373144
          0398c55a-4cf9-4c94-a188-758dd261f0ee
          History
          Categories
          Article

          Ku80,PARP1,PARP2,H2AX,DNA-PKcs,double-strand breaks
          Ku80, PARP1, PARP2, H2AX, DNA-PKcs, double-strand breaks

          Comments

          Comment on this article