BCAT1 Associates with DNA Repair Proteins KU70 and KU80 and Contributes to Regulate DNA Repair in T-Cell Acute Lymphoblastic Leukemia (T-ALL)

被引:1
作者
Tosello, Valeria [1 ]
Rompietti, Chiara [2 ]
Papathanassiu, Adonia E. [3 ]
Arrigoni, Giorgio [4 ,5 ,6 ]
Piovan, Erich [2 ,7 ]
机构
[1] Veneto Inst Oncol IOV, Basic & Translat Oncol Unit, IRCCS, I-35127 Padua, Italy
[2] Veneto Inst Oncol IOV, Immunol & Mol Oncol Diagnost, IRCCS, I-35128 Padua, Italy
[3] Ergon Pharmaceut LLC, Washington, DC 20011 USA
[4] Univ Padua, Dept Biomed Sci, I-35122 Padua, Italy
[5] Univ Padua, Prote Ctr, I-35131 Padua, Italy
[6] Azienda Osped Padua, I-35131 Padua, Italy
[7] Univ Padua, Dept Surg Oncol & Gastroenterol, I-35128 Padua, Italy
关键词
T-cell lymphoblastic leukemia; metabolism; BCAT1; leukemia growth; C-MYC; NOTCH1; DAMAGE; ACETYLATION; ACTIVATION;
D O I
10.3390/ijms252413571
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Increased expression of branched-chain amino acid (BCAA) transaminase 1 (BCAT1) often correlates with tumor aggressiveness and drug resistance in cancer. We have recently reported that BCAT1 was overexpressed in a subgroup of T-cell acute lymphoblastic (T-ALL) samples, especially those with NOTCH1 activating mutations. Interestingly, BCAT1-depleted cells showed pronounced sensitivity to DNA-damaging agents such as etoposide; however, how BCAT1 regulates this sensitivity remains uncertain. Here, we provide further clues on its chemo-sensitizing effect. Indeed, BCAT1 protein regulates the non-homologous end joining (c-NHEJ) DNA repair pathway by physically associating with the KU70/KU80 heterodimer. BCAT1 inhibition during active repair of DNA double-strand breaks (DSBs) led to increased KU70/KU80 acetylation and impaired c-NHEJ repair, a dramatic increase in DSBs, and ultimately cell death. Our results suggest that, in T-ALL, BCAT1 possesses non-metabolic functions that confer a drug resistance mechanism and that targeting BCAT1 activity presents a novel strategy to improve chemotherapy response in T-ALL patients.
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页数:19
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