Abstract
Hypoxia-induced replication stress is one of the most physiologically relevant signals known to activate ATM in tumors. Recently, the ATM interactor (ATMIN) was identified as critical for replication stress-induced activation of ATM in response to aphidicolin and hydroxyurea. This suggests an essential role for ATMIN in ATM regulation during hypoxia, which induces replication stress. However, ATMIN also has a role in base excision repair, a process that has been demonstrated to be repressed and less efficient in hypoxic conditions. Here, we demonstrate that ATMIN is dispensable for ATM activation in hypoxia and in contrast to ATM, does not affect cell survival and radiosensitivity in hypoxia. Instead, we show that in hypoxic conditions ATMIN expression is repressed. Repression of ATMIN in hypoxia is mediated by both p53 and HIF-1α in an oxygen dependent manner. The biological consequence of ATMIN repression in hypoxia is decreased expression of the target gene, DYNLL1. An expression signature associated with p53 activity was negatively correlated with DYNLL1 expression in patient samples further supporting the p53 dependent repression of DYNLL1. Together, these data demonstrate multiple mechanisms of ATMIN repression in hypoxia with consequences including impaired BER and down regulation of the ATMIN transcriptional target, DYNLL1.
Highlights
Treatment, and for recruitment of 53BP1 to foci after both MMS and APH treatment[22,26,27,28,29]
The cells were exposed to hypoxia (< 0.1% O2) for 3 h, as we have shown previously that ATM is activated during this period[13]
As HIF-1 has been demonstrated to play a role in the repression of other DNA repair proteins in hypoxia we investigated a potential role for HIF-1 in ATMIN repression[11]
Summary
Treatment, and for recruitment of 53BP1 to foci after both MMS and APH treatment[22,26,27,28,29]. ATMIN, which includes a Zn2+ finger domain, has been shown to act as a transcription factor driving expression of a very limited number of target genes including DYNLL1, which plays an important role in lung morphogenesis[28,29]. The mechanism of repression is complex and is in part dependent on both HIF-1 and p53, demonstrating that repression of ATMIN is critical to the biological response to hypoxia. While this may be due to the role of ATMIN in DNA repair, we demonstrate for the first time that expression of the ATMIN target gene DYNLL1 is altered in response to hypoxia
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