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BCLAF1 is a radiation-induced H2AX-interacting partner involved in γH2AX-mediated regulation of apoptosis and DNA repair

Journal Article · · Cell Death and Disease
 [1];  [2];  [3];  [4];  [5]
  1. Univ. of North Carolina, Chapel Hill, NC (United States). Dept. of Biochemistry and Biophysics; DOE/OSTI
  2. 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
  3. 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
  4. Univ. of North Carolina, Chapel Hill, NC (United States). Dept. of Biochemistry and Biophysics
  5. 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
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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:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; National Institutes of Health (NIH
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

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DNA damage and synaptic and behavioural disorders in glucose-6-phosphate dehydrogenase-deficient mice journal January 2020
miR-194-5p/BCLAF1 deregulation in AML tumorigenesis journal February 2017
Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain journal January 2013
Enhanced breast cancer progression by mutant p53 is inhibited by the circular RNA circ-Ccnb1 journal May 2018
Breast Cancer Induced by X-Ray Mammography Screening? A Review Based on Recent Understanding of Low-Dose Radiobiology journal November 2015
Global Characterization of Differential Gene Expression Profiles in Mouse Vγ1+ and Vγ4+ γδ T Cells journal November 2014
Functions and Potential Applications of Circular RNAs in Cancer Stem Cells journal June 2019
Tribbles Homolog 3 Involved in Radiation Response of Triple Negative Breast Cancer Cells by Regulating Notch1 Activation journal January 2019
The nuclear envelope LEM-domain protein emerin journal July 2013
Additional file 1 of Bcl-2-associated transcription factor 1 Ser290 phosphorylation mediates DNA damage response and regulates radiosensitivity in gastric cancer image January 2021
Additional file 2 of Bcl-2-associated transcription factor 1 Ser290 phosphorylation mediates DNA damage response and regulates radiosensitivity in gastric cancer image January 2021
Additional file 3 of Bcl-2-associated transcription factor 1 Ser290 phosphorylation mediates DNA damage response and regulates radiosensitivity in gastric cancer image January 2021
Additional file 4 of Bcl-2-associated transcription factor 1 Ser290 phosphorylation mediates DNA damage response and regulates radiosensitivity in gastric cancer dataset January 2021
NEK5 interacts with topoisomerase IIβ and is involved in the DNA damage response induced by etoposide
  • Melo‐Hanchuk, Talita Diniz; Slepicka, Priscila Ferreira; Pelegrini, Alessandra Luiza
  • Journal of Cellular Biochemistry, Vol. 120, Issue 10 https://doi.org/10.1002/jcb.28943
journal May 2019
Erratum: miR-194-5p/BCLAF1 deregulation in AML tumorigenesis journal December 2017
Bclaf1 promotes angiogenesis by regulating HIF-1α transcription in hepatocellular carcinoma journal October 2018
Destabilization of the MiniChromosome Maintenance (MCM) complex modulates the cellular response to DNA double strand breaks journal December 2018
Differential gene expression profile and altered cytokine secretion of thyroid cancer cells in space journal October 2013
Platelet‐derived microparticles promote endothelial cell proliferation in hypertension via miR‐142–3p journal February 2018
Bclaf1 critically regulates the type I interferon response and is degraded by alphaherpesvirus US3 posted_content August 2018
Transcriptome analyses of rhesus monkey preimplantation embryos reveal a reduced capacity for DNA double-strand break repair in primate oocytes and early embryos journal February 2017
B‐cell lymphoma‐2‐associated transcription factor 1 is overexpressed and contributes to sorafenib resistance in hepatocellular carcinoma journal July 2019
Bclaf1 critically regulates the type I interferon response and is degraded by alphaherpesvirus US3 journal January 2019
Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain text January 2013

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
DNA damage and repair
DNA damage/repair
apoptosis
cell biology
cell cycle
gene regulation
histone H2AX
histone variants