Open AccessPML nuclear body disruption impairs DNA double-strand break sensing and repair in APL
Author(s) -
Alessandra di Masi,
Domenica Cilli,
Francesco Berardinelli,
Anna Talarico,
Isabella Pallavicini,
Rosa Pennisi,
Stefano Leone,
Antonio Antoccia,
Nélida I. Noguera,
Francesco LoCoco,
Paolo Ascenzi,
Saverio Minucci,
Clara Nervi
Publication year - 2016
Publication title -
cell death and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.482
H-Index - 111
ISSN - 2041-4889
DOI - 10.1038/cddis.2016.115
Subject(s) - microbiology and biotechnology , dna damage , dna repair , dna , biology , chemistry , genetics , computational biology
Proteins involved in DNA double-strand break (DSB) repair localize within the promyelocytic leukemia nuclear bodies (PML-NBs), whose disruption is at the root of the acute promyelocytic leukemia (APL) pathogenesis. All- trans -retinoic acid (RA) treatment induces PML-RAR α degradation, restores PML-NB functions, and causes terminal cell differentiation of APL blasts. However, the precise role of the APL-associated PML-RAR α oncoprotein and PML-NB integrity in the DSB response in APL leukemogenesis and tumor suppression is still lacking. Primary leukemia blasts isolated from APL patients showed high phosphorylation levels of H2AX ( γ -H2AX), an initial DSBs sensor. By addressing the consequences of ionizing radiation (IR)-induced DSB response in primary APL blasts and RA-responsive and -resistant myeloid cell lines carrying endogenous or ectopically expressed PML-RAR α , before and after treatment with RA, we found that the disruption of PML-NBs is associated with delayed DSB response, as revealed by the impaired kinetic of disappearance of γ -H2AX and 53BP1 foci and activation of ATM and of its substrates H2AX, NBN, and CHK2. The disruption of PML-NB integrity by PML-RAR α also affects the IR-induced DSB response in a preleukemic mouse model of APL in vivo . We propose the oncoprotein-dependent PML-NB disruption and DDR impairment as relevant early events in APL tumorigenesis.