ARF triggers senescence in Brca2-deficient cells by altering the spectrum of p53 transcriptional targets

Abstract

ARF is a tumour suppressor activated by oncogenic stress, which stabilizes p53. Although p53 is a key component of the response to DNA damage, a similar function for ARF has not been ascribed. Here we show that primary mouse and human cells lacking the tumour suppressor BRCA2 accumulate DNA damage, which triggers checkpoint signalling and ARF activation. Furthermore, senescence induced by Brca2 deletion in primary mouse and human cells is reversed by the loss of ARF, a phenotype recapitulated in cells lacking RAD51. Surprisingly, ARF is not necessary for p53 accumulation per se but for altering the spectrum of genes activated by this transcription factor. Specifically, ARF enables p53 transcription of Dusp4 and Dusp7, which encode a pair of phosphatases known to inactivate the MAP kinases ERK1/2. Our results ascribe a previously unanticipated function to the ARF tumour suppressor in genome integrity, controlled by replicative stress and ATM/ATR-dependent checkpoint responses.

MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells

“…In addition, BRCA2 plays a role during mitosis where it regulates the metaphase to anaphase transition by sustaining spindle assembly checkpoint (SAC) via BubR1 acetylation5. Upon BRCA2 gene deletion, primary cells succumb to spontaneous double strand break (DSB) accumulation and checkpoint activation, which channel cells into senescence and apoptosis67. Cancer cells lacking BRCA2, however, acquire additional mutations, for example in tumour suppressor genes such as p53, which together with upregulation of error-prone DSB repair pathways sustain replication and proliferation8.…”

DNA double strand break responses and chromatin alterations within the aging cell

“…The altered transcriptional activity of p53 leads to expression of the dual specificity phosphatases 4 and 7 (DUSP4 and DUSP7). Both enzymes inactivate the MAP kinases ERK1/2 through dephosphorylation, thereby initiating permanent cell cycle arrest [67]. Cellular stresses that do not involve DNA damage as their primary mode of action, such as physiological stress, culture conditions and chromatin perturbing agents, can lead to senescence via the induction of p16 (CDKN2A) [68][69][70][71][72][73].…”

ARF Confers a Context-Dependent Response to Chemotherapy in Muscle-Invasive Bladder Cancer

“…Furthermore, cisplatin sensitivity has also been shown to correlate with alterations in DNA repair in patients with bladder cancer (4,5). Given that ARF is a sensor for regulating DNA damage response (54,55), it will be of interest to assess the relationship of ARF to DNA damage in these mutational contexts.…”