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Checkpoints modulation by the human T-lymphotropic virus type 1 (HTLV-1) Tax protein : towards new therapeutic approaches
Carpentier, Alexandre; Barez, Pierre-Yves; Boxus, Mathieu et al.
2015Séminaire des chercheurs Télévie 2015
 

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Keywords :
HTLV-1; Tax; DNA Damage
Abstract :
[en] HTLV-1 infects approximately 20 million people worldwide and causes several diseases. This virus is responsible for the adult T-cell leukemia (ATL) and for a chronic neuropathology (TSP/HAM). There is currently no satisfactory treatment for these diseases. Among the proteins encoded by HTLV-1, Tax appears to play an important role in the mechanisms leading to pathogenicity. We are interested in the mechanisms of cell transformation by HTLV-1 and more particularly in the interplay between the viral Tax oncoprotein and the DNA damage response (DDR). We demonstrate that transient expression of Tax results in DNA damage, cell cycle arrest and activation of the ATM-Chk2-p53 axis of the DDR. In fibroblasts, cell cycle arrest occurs at the G1 and G2 phases depending on the p53 background. Despite Tax expression hampers cell cycle progression, neither pro-apoptotic nor pro-senescent effects are observed. In contrast, HTLV-1 infected lymphocytes proliferate continuously and appear to be adapted to the checkpoints. This mechanism allows infected lymphocytes to proliferate despite the presence of genomic lesions. Those cells might thus rely on effective DNA repair mechanisms. Indeed, we show that Tax expressing cells activate the error free repair mechanism homologous recombination (HR). Inhibition of ATM, involved in DDR and DNA repair by HR, impedes Tax-mediated cellular transformation. Depending on these observations, we propose a novel therapeutic approach based on the principle of synthetic lethality.
Disciplines :
Oncology
Author, co-author :
Carpentier, Alexandre ;  Université de Liège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Biologie cell. et moléc.
Barez, Pierre-Yves ;  Université de Liège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Biologie cell. et moléc.
Boxus, Mathieu
Willems, Luc  ;  Université de Liège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Biologie cell. et moléc.
Language :
English
Title :
Checkpoints modulation by the human T-lymphotropic virus type 1 (HTLV-1) Tax protein : towards new therapeutic approaches
Publication date :
11 February 2015
Number of pages :
A0
Event name :
Séminaire des chercheurs Télévie 2015
Event organizer :
Ecole Doctorale en Cancérologie Expérimentale et Université Libre de Bruxelles (ULB)
Event place :
Bruxelles, Belgium
Event date :
11 février 2015
Available on ORBi :
since 22 May 2015

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