期刊
JOURNAL OF CELLULAR BIOCHEMISTRY
卷 113, 期 5, 页码 1787-1799出版社
WILEY
DOI: 10.1002/jcb.24050
关键词
ACUTE PROMYELOCYTIC LEUKEMIA; PML NUCLEAR BODIES; DNA REPAIR; HOMOLOGOUS RECOMBINATION; ALL-TRANS RETINOIC ACID; ARSENIC TRIOXIDE
资金
- National Cancer Institute [CA122795]
- New Jersey Commission on Science and Technology
- Cancer Institute of New Jersey
The PML protein and PML nuclear bodies (PML-NB) are implicated in multiple cellular functions relevant to tumor suppression, including DNA damage response. In most cases of acute promyelocytic leukemia, the PML and retinoic acid receptor alpha (RARA) genes are translocated, resulting in expression of oncogenic PML-RARa fusion proteins. PML-NB fail to form normally, and promyelocytes remain in an undifferentiated, abnormally proliferative state. We examined the involvement of PML protein and PML-NB in homologous recombinational repair (HRR) of chromosomal DNA double-strand breaks. Transient overexpression of wild-type PML protein isoforms produced hugely enlarged or aggregated PML-NB and reduced HRR by similar to 2-fold, suggesting that HRR depends to some extent upon normal PML-NB structure. Knockdown of PML by RNA interference sharply attenuated formation of PML-NB and reduced HRR by up to 20-fold. However, PML-knockdown cells showed apparently normal induction of H2AX phosphorylation and RAD51 foci after DNA damage by ionizing radiation. These findings indicate that early steps in HRR, including recognition of DNA double-strand breaks, initial processing of ends, and assembly of single-stranded DNA/RAD51 nucleoprotein filaments, do not depend upon PML-NB. The HRR deficit in PML-depleted cells thus reflects inhibition of later steps in the repair pathway. Expression of PML-RARa fusion proteins disrupted PML-NB structure and reduced HRR by up to 10-fold, raising the possibility that defective HRR and resulting genomic instability may figure in the pathogenesis, progression and relapse of acute promyelocytic leukemia. J. Cell. Biochem. 113: 17871799, 2012. (C) 2011 Wiley Periodicals, Inc.
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