共 49 条
A new pathway that regulates 53BP1 stability implicates Cathepsin L and vitamin D in DNA repair
被引:87
作者:
Gonzalez-Suarez, Ignacio
[1
]
Redwood, Abena B.
[1
]
Grotsky, David A.
[1
]
Neumann, Martin A.
[1
]
Cheng, Emily H-Y
[2
]
Stewart, Colin L.
[3
]
Dusso, Adriana
[1
,4
]
Gonzalo, Susana
[1
]
机构:
[1] Washington Univ, Sch Med, Dept Radiat Oncol, Radiat & Canc Biol Div, St Louis, MO 63108 USA
[2] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA
[3] Immunos Singapore, Inst Med Biol, Singapore, Singapore
[4] IRB Lleida, Div Expt Nephrol, Lleida, Spain
关键词:
DNA repair;
genomic instability;
protein degradation;
vitamin D;
DOUBLE-STRAND BREAKS;
A-TYPE LAMINS;
CLASS-SWITCH RECOMBINATION;
DAMAGE-RESPONSE;
HEMATOLOGIC MALIGNANCIES;
CYSTEINE CATHEPSINS;
NUCLEAR LAMINS;
CANCER CELLS;
GENE;
MECHANISMS;
D O I:
10.1038/emboj.2011.225
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:
Genomic instability due to telomere dysfunction and defective repair of DNA double-strand breaks (DSBs) is an underlying cause of ageing-related diseases. 53BP1 is a key factor in DNA DSBs repair and its deficiency is associated with genomic instability and cancer progression. Here, we uncover a novel pathway regulating the stability of 53BP1. We demonstrate an unprecedented role for the cysteine protease Cathepsin L (CTSL) in the degradation of 53BP1. Overexpression of CTSL in wild-type fibroblasts leads to decreased 53BP1 protein levels and changes in its cellular distribution, resulting in defective repair of DNA DSBs. Importantly, we show that the defects in DNA repair associated with 53BP1 deficiency upon loss of A-type lamins are due to upregulation of CTSL. Furthermore, we demonstrate that treatment with vitamin D stabilizes 53BP1 and promotes DNA DSBs repair via inhibition of CTSL, providing an as yet unsuspected link between vitamin D action and DNA repair. Given that CTSL upregulation is a hallmark of cancer and progeria, regulation of this pathway could be of great therapeutic significance for these diseases. The EMBO Journal (2011) 30, 3383-3396. doi:10.1038/emboj.2011.225; Published online 12 July 2011
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页码:3383 / 3396
页数:14
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