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Accumulation of Pax2 transactivation domain interaction protein (PTIP) at sites of DNA breaks via RNF8-dependent pathway is required for cell survival after DNA damage.

Genomic stability in eukaryotic cells is maintained by the coordination of multiple cellular events including cell cycle checkpoint, DNA repair, transcription, and apoptosis after DNA damage. Pax2 transactivation domain interaction protein (PTIP), a protein that contains six BRCT domains, has been implicated in DNA damage response. In this study we showed that recruitment of PTIP to damaged chromatin depends on DNA damage signaling proteins gammaH2AX.MDC1.RNF8, which in turn facilitates sustained localization of PA1 (PTIP-associated protein 1) to sites of DNA break. Similar to PTIP, depletion of PA1 increases cellular sensitivity to ionizing radiation. Furthermore, we demonstrated that the N-terminal PA1 binding domain and the C-terminal focus-localization domain of PTIP are critical for PTIP function in DNA damage repair. Interestingly, although PTIP and PA1 associate with MLL (mixed lineage leukemia) complexes and participate in transcriptional regulation, this function of PTIP.PA1 in DNA damage response is likely to be independent of the MLL complexes. Taken together, we propose that a subset of PTIP.PA1 complex is recruited to DNA damage sites via the RNF8-dependent pathway and is required for cell survival in response to DNA damage.

Pubmed ID: 19124460

Authors

  • Gong Z
  • Cho YW
  • Kim JE
  • Ge K
  • Chen J

Journal

The Journal of biological chemistry

Publication Data

March 13, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA089239
  • Agency: NCI NIH HHS, Id: CA092312
  • Agency: NCI NIH HHS, Id: CA100109
  • Agency: NCI NIH HHS, Id: R01 CA092312
  • Agency: NCI NIH HHS, Id: R01 CA092312-09
  • Agency: NCI NIH HHS, Id: R01 CA100109
  • Agency: NCI NIH HHS, Id: R01 CA100109-07
  • Agency: Intramural NIH HHS, Id: Z01 DK047055-01
  • Agency: Intramural NIH HHS, Id: Z01 DK047055-02
  • Agency: Intramural NIH HHS, Id: Z01 DK075003-04
  • Agency: Intramural NIH HHS, Id: Z01 DK075003-05
  • Agency: Intramural NIH HHS, Id: Z99 DK999999
  • Agency: Intramural NIH HHS, Id: ZIA DK075003-08
  • Agency: NIDDK NIH HHS, Id: ZIADK047055-03
  • Agency: NIDDK NIH HHS, Id: ZIADK075003-06
  • Agency: NIDDK NIH HHS, Id: ZIADK075017-01

Mesh Terms

  • Animals
  • Carrier Proteins
  • Cell Survival
  • Chromatin
  • DNA Breaks
  • DNA-Binding Proteins
  • Gamma Rays
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase
  • Histones
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Multiprotein Complexes
  • Myeloid-Lymphoid Leukemia Protein
  • Nuclear Proteins
  • Protein Structure, Tertiary
  • Trans-Activators