TIE2-mediated tyrosine phosphorylation of H4 regulates DNA damage response by recruiting ABL1

Authors

Mohammad B. Hossain, University of Texas MD Anderson Cancer Center
Rehnuma Shifat, University of Texas MD Anderson Cancer Center
David G. Johnson, Virginia Harris Cockrell Cancer Research Center at The University of Texas MD Anderson Cancer Center
Mark T. Bedford, Virginia Harris Cockrell Cancer Research Center at The University of Texas MD Anderson Cancer Center
Konrad R. Gabrusiewicz, University of Texas MD Anderson Cancer Center
Nahir Cortes-Santiago, University of Texas MD Anderson Cancer Center
Xuemei Luo, UT Medical Branch at Galveston
Zhimin Lu, University of Texas MD Anderson Cancer Center
Ravesanker Anagnostou, University of Toronto
Jessica Brian, Holland Bloorview Kids Rehabilitation Hospital

Document Type

Article

Publication Date

4-1-2016

Journal

Science Advances

Volume

2

Issue

4

URL with Digital Object Identifier

10.1126/sciadv.1501290

Abstract

DNA repair pathways enable cancer cells to survive DNA damage induced after genotoxic therapies. Tyrosine kinase receptors (TKRs) have been reported as regulators of the DNA repair machinery. TIE2 is a TKR overexpressed in human gliomas at levels that correlate with the degree of increasing malignancy. Following ionizing radiation, TIE2 translocates to the nucleus, conferring cells with an enhanced nonhomologous end-joining mechanism of DNA repair that results in a radioresistant phenotype. Nuclear TIE2 binds to key components of DNA repair and phosphorylates H4 at tyrosine 51, which, in turn, is recognized by the proto-oncogene ABL1, indicating a role for nuclear TIE2 as a sensor for genotoxic stress by action as a histone modifier. H4Y51 constitutes the first tyrosine phosphorylation of core histones recognized by ABL1, defining this histone modification as a direct signal to couple genotoxic stress with the DNA repair machinery.