Che-1 phosphorylation by ATM/ATR and Chk2 kinases activates p53 transcription and the G2/M checkpoint

Abstract

Che-1 is a RNA polymerase II-binding protein involved in the transcription of E2F target genes and induction of cell proliferation. Here we show that Che-1 contributes to DNA damage response and that its depletion sensitizes cells to anticancer agents. The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. Interestingly, it has a profound effect on the basal expression of p53, which is preserved following DNA damage. Notably, Che-1 contributes to the maintenance of the G2/M checkpoint induced by DNA damage. These findings identify a mechanism by which checkpoint kinases regulate responses to DNA damage.

Che-1 activates XIAP expression in response to DNA damage

“…Moreover, microarray and chromatin immunoprecipitation (ChIP) analyses show that Che-1 activates the transcription of p53 and consequently of several p53 target genes, identifying a new pathway by which ATM and Chk2 modulate p53 levels. 18 More importantly, we found that Che-1 inhibition intensifies the cytotoxicity of anticancer drugs that damage the DNA and, in such way, can revert chemoresistance of several tumor cell lines. 18 In this report, we describe that in response to genotoxic stress, Che-1 upregulates XIAP expression and this activation is required for Che-1 antiapoptotic activity.…”

“…18 More importantly, we found that Che-1 inhibition intensifies the cytotoxicity of anticancer drugs that damage the DNA and, in such way, can revert chemoresistance of several tumor cell lines. 18 In this report, we describe that in response to genotoxic stress, Che-1 upregulates XIAP expression and this activation is required for Che-1 antiapoptotic activity. Moreover, we show that in vivo depletion of Che-1 is able to sensitize HCT116 tumors to antineoplastic drugs.…”

“…17 Recently, we showed that DNA damage by different genotoxic agents is associated with Che-1 phosphorylation and extended half-life. 18 These posttranslational modifications are induced by ataxia telangiectasia mutated protein (ATM) and checkpoint kinase 2 (Chk2), which phosphorylate Che-1 on specific residues and are functionally linked to DNA damage-induced G 2 /M checkpoint. Moreover, microarray and chromatin immunoprecipitation (ChIP) analyses show that Che-1 activates the transcription of p53 and consequently of several p53 target genes, identifying a new pathway by which ATM and Chk2 modulate p53 levels.…”

ZIP kinase plays a crucial role in androgen receptor-mediated transcription

“…Most recently, AATF/Che1 was shown to be involved in the DNA damage response. Upon DNA damage, AATF/ Che1 is phosphorylated by ataxia telangiectasia mutated (ATM) and checkpoint kinase Chk-2 and upregulates p53 (Bruno et al, 2006). Whether in this case AATF/Che1 functions as a bona fide transcription factor or as coactivator is not clear.…”

AATF: A new actor in the complex world of mTOR

“…5,6 These modifications induce translocation of AATF from the cytoplasm to the nucleus, lead to AATF stabilization and accumulation by increasing its resistance to proteasome degradation, and transfer this protein from pathways regulating cell cycle progression to those involved in cell cycle arrest and survival. 5,6 In our recent study we demonstrate that AATF is activated by checkpoint kinases not only when DNA damage is present, but also in response to other kinds of stress such as hypoxia and glucose deprivation. Once activated, AATF controls mTORC1 and mTORC2 activities by inducing expression of DDIT4 and Deptor, 2 important inhibitors of mTOR.…”