BCLAF1 is a radiation-induced H2AX-interacting partner involved in γH2AX-mediated regulation of apoptosis and DNA repair
Journal Article
·
· Cell Death and Disease
- Univ. of North Carolina, Chapel Hill, NC (United States). Dept. of Biochemistry and Biophysics; DOE/OSTI
- Univ. of North Carolina, Chapel Hill, NC (United States). Dept. of Biochemistry and Biophysics; Univ. of North Carolina, Chapel Hill, NC (United States). Center for Technology Development of proteomics; Fudan Univ., Shanghai (China). Dept. of Chemistry
- Univ. of North Carolina, Chapel Hill, NC (United States). Dept. of Biochemistry and Biophysics; Univ. of North Carolina, Chapel Hill, NC (United States). Center for Technology Development of proteomics
- Univ. of North Carolina, Chapel Hill, NC (United States). Dept. of Biochemistry and Biophysics
- Univ. of North Carolina, Chapel Hill, NC (United States). Dept. of Biochemistry and Biophysics; Univ. of North Carolina, Chapel Hill, NC (United States). Lineberger Comprehensive Cancer Center; Univ. of North Carolina, Chapel Hill, NC (United States). Center for Technology Development of proteomics; Fudan Univ., Shanghai (China). Dept. of Chemistry
H2AX, a histone H2A variant, has a key role in the cellular response to DNA double-strand breaks (DSBs). H2AX senses DSBs through rapid serine 139 phosphorylation, concurrently leading to the formation of phospho-(c)H2AX foci with various proteins. However, in the cells with different sensitivity to ionizing radiation (IR)-induced DSBs, still incomplete are those specific proteins selectively recruited by cH2AX to decide different cell fates. Because the abundance of cH2AX indicates the extent of DSBs, we first identified IR-induced dose-dependent H2AX-interacting partners and found that Bcl-2-associated transcription factor 1 (BCLAF1/Btf) showed enhanced association with cH2AX only under high-dose radiation. In acutely irradiated cells, BCLAF1 promoted apoptosis of irreparable cells through disturbing p21-mediated inhibition of Caspase/cyclin E-dependent, mitochondrial-mediated pathways. Meanwhile, BCLAF1 co-localized with cH2AX foci in nuclei and stabilized the Ku70/DNAPKcs complex therein, facilitating non-homologous end joining (NHEJ)-based DSB repair in surviving cells. In tumor cells, BCLAF1 was intrinsically suppressed, leading to formation of anti-apoptotic Ku70–Bax complexes and disruption of Ku70/DNAPKcs complexes, all of which contribute to tumor-associated apoptotic resistance and cell survival with defective NHEJ DNA repair. For the first time, our studies reveal that, based on the extent of DNA damage, BCLAF1 is involved in the cH2AX-mediated regulation of apoptosis and DNA repair, and is a cH2AX-interacting tumor suppressor.
- Research Organization:
- Univ. of North Carolina, Chapel Hill, NC (United States)
- Sponsoring Organization:
- National Institutes of Health (NIH; USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
- Grant/Contract Number:
- FG02-07ER64422
- OSTI ID:
- 1623743
- Journal Information:
- Cell Death and Disease, Journal Name: Cell Death and Disease Journal Issue: 7 Vol. 3; ISSN 2041-4889
- Publisher:
- Nature Publishing GroupCopyright Statement
- Country of Publication:
- United States
- Language:
- English
Similar Records
Defective chromatin recruitment and retention of NHEJ core components in human tumor cells expressing a Cyclin E fragment
The HINT1 tumor suppressor regulates both γ-H2AX and ATM in response to DNA damage
Accumulation of p21 proteins at DNA damage sites independent of p53 and core NHEJ factors following irradiation
Journal Article
·
Sun Sep 08 20:00:00 EDT 2013
· Nucleic Acids Research
·
OSTI ID:1625528
The HINT1 tumor suppressor regulates both γ-H2AX and ATM in response to DNA damage
Journal Article
·
Sun Oct 12 20:00:00 EDT 2008
· Journal of Cell Biology
·
OSTI ID:1625146
Accumulation of p21 proteins at DNA damage sites independent of p53 and core NHEJ factors following irradiation
Journal Article
·
Fri Aug 19 00:00:00 EDT 2011
· Biochemical and Biophysical Research Communications
·
OSTI ID:22207451