DNA damage stress response in germ cells: role of c-Abl and clinical implications

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摘要：

Cells experiencing DNA damage undergo a complex response entailing cell-cycle arrest, DNA repair and apoptosis, the relative importance of the three being modulated by the extent of the lesion. The observation that Abl interacts in the nucleus with several proteins involved in different aspects of DNA repair has led to the hypothesis that this kinase is part of the damage-sensing mechanism. However, the mechanistic details underlying the role of Abl in DNA repair remain unclear. Here, I will review the evidence supporting our current understanding of Abl activation following DNA insults, while focusing on the relevance of these mechanisms in protecting DNA-injured germ cells. Early studies have shown that Abl transcripts are highly expressed in the germ line. Abl-deficient mice exhibit multiple abnormalities, increased perinatal mortality and reduced fertility. Recent findings have implicated Abl in a cisplatin-induced signaling pathway eliciting death of immature oocytes. A p53-related protein, TAp63, is an important immediate downstream effector of this pathway. Of note, pharmacological inhibition of Abl protects the ovarian reserve from the toxic effects of cisplatin. This suggests that the extent of Abl catalytic outputs may shift the balance between survival (likely through DNA repair) and activation of a death response. Taken together, these observations are consistent with the evolutionary conserved relationship between DNA damage and activation of the p53 family of transcription factors, while shedding light on the key role of Abl in dictating the fate of germ cells upon genotoxic insults.

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关键词：

c-Abl tyrosine kinase DNA damage response germ cells TAp63 chemotherapy

DOI：

10.1038/onc.2010.410

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年份：

2010