The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

Abstract

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.

Gata6 promotes hair follicle progenitor cell renewal by genome maintenance during proliferation

“…In conclusion, our current study adds to very recent publications (Lamm et al , ; Petroni et al , ) in suggesting that highly proliferative cells, such as the progenitor cells of the hair follicle and the brain, as well as embryonic stem cells employ developmentally controlled transcription factors (i.e. SRF, MYCN, and now Gata6) to protect against increased risk of genotoxic stress associated with rapid proliferation.…”

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

“…Around 50% of HR-NB have an amplification of the MYCN oncogene, which drives proliferation and causes replication stress (117). MYCN also transcriptionally upregulates many proteins involved in DNA DSB repair, including components of the MRE11-RAD50-NBLS1 (MRN) complex (118,119), alternative NHEJ (alt-NHEJ) (120), and Bloom syndrome (BLM) helicase (121), and the cell cycle checkpoint protein CHK1 (117,122). Upregulation of these genes likely provide MYCNdriven tumors the ability to tolerate higher levels of DNA damage and replication stress.…”

Family matters: How MYC family oncogenes impact small cell lung cancer

“…70,73,74 Similarly, MYCN has also been reported to induce DDR signaling in neuroblastoma cells, 13,75 which could be due to increased replicative stress. 76 No reports of similar effects of MYCL overexpression are available to date. Intriguingly, despite its indisputable central role in promoting proliferation, high levels of MYC can also induce apoptosis, 77,78 and overexpression of all 3 MYC family members was found to induce apoptosis upon IL-3 withdrawal in 32D myeloid cells.…”