Loss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma

Abstract Genetic aberrations are present in the ATRX gene in older high-risk neuroblastoma (NB) patients with very poor clinical outcomes. Its loss-of-function (LoF) facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells and is strongly linked to replication stress (RS) an...

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Autores principales:	Jesmin Akter, Yutaka Katai, Parvin Sultana, Hisanori Takenobu, Masayuki Haruta, Ryuichi P. Sugino, Kyosuke Mukae, Shunpei Satoh, Tomoko Wada, Miki Ohira, Kiyohiro Ando, Takehiko Kamijo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/a2daa5a4a53642579e6bb90d160a40c5
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spelling	oai:doaj.org-article:a2daa5a4a53642579e6bb90d160a40c52021-11-08T10:45:41ZLoss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma10.1038/s41389-021-00363-62157-9024https://doaj.org/article/a2daa5a4a53642579e6bb90d160a40c52021-11-01T00:00:00Zhttps://doi.org/10.1038/s41389-021-00363-6https://doaj.org/toc/2157-9024Abstract Genetic aberrations are present in the ATRX gene in older high-risk neuroblastoma (NB) patients with very poor clinical outcomes. Its loss-of-function (LoF) facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells and is strongly linked to replication stress (RS) and DNA damage through G-quadruplex (G4) DNA secondary structures. However, limited information is available on ATRX alteration-related NB tumorigenesis. We herein knocked out (KO) ATRX in MYCN-amplified (NGP) and MYCN single copy (SK-N-AS) NB cells with wild-type (wt) and truncated TP53 at the C terminus, respectively, using CRISPR/Cas9 technologies. The loss of ATRX increased DNA damage and G4 formation related to RS in TP53 wt isogenic ATRX KO NGP cells, but not in SK-N-AS clones. A gene set enrichment analysis (GSEA) showed that the gene sets related to DNA double-strand break repair, negative cell cycle regulation, the G2M checkpoint, and p53 pathway activation were enriched in NGP clones. The accumulation of DNA damage activated the ATM/CHK2/p53 pathway, leading to cell cycle arrest in NGP clones. Interestingly, ATRX loss did not induce RS related to DNA damage response (DDR) in TP53-truncated SK-N-AS cells. p53 inactivation abrogated cell cycle arrest and reduced G4 accumulation in NGP clones. The loss of p53 also induced G4 DNA helicases or Fanconi anemia group D2 protein (FANCD2) with ATRX deficiency, suggesting that ATRX maintained genome integrity and p53 deficiency attenuated RS-induced DNA damage in NB cells featuring inactivated ATRX by regulating DNA repair mechanisms and replication fork stability.Jesmin AkterYutaka KataiParvin SultanaHisanori TakenobuMasayuki HarutaRyuichi P. SuginoKyosuke MukaeShunpei SatohTomoko WadaMiki OhiraKiyohiro AndoTakehiko KamijoNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncogenesis, Vol 10, Iss 11, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Jesmin Akter Yutaka Katai Parvin Sultana Hisanori Takenobu Masayuki Haruta Ryuichi P. Sugino Kyosuke Mukae Shunpei Satoh Tomoko Wada Miki Ohira Kiyohiro Ando Takehiko Kamijo Loss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma
description	Abstract Genetic aberrations are present in the ATRX gene in older high-risk neuroblastoma (NB) patients with very poor clinical outcomes. Its loss-of-function (LoF) facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells and is strongly linked to replication stress (RS) and DNA damage through G-quadruplex (G4) DNA secondary structures. However, limited information is available on ATRX alteration-related NB tumorigenesis. We herein knocked out (KO) ATRX in MYCN-amplified (NGP) and MYCN single copy (SK-N-AS) NB cells with wild-type (wt) and truncated TP53 at the C terminus, respectively, using CRISPR/Cas9 technologies. The loss of ATRX increased DNA damage and G4 formation related to RS in TP53 wt isogenic ATRX KO NGP cells, but not in SK-N-AS clones. A gene set enrichment analysis (GSEA) showed that the gene sets related to DNA double-strand break repair, negative cell cycle regulation, the G2M checkpoint, and p53 pathway activation were enriched in NGP clones. The accumulation of DNA damage activated the ATM/CHK2/p53 pathway, leading to cell cycle arrest in NGP clones. Interestingly, ATRX loss did not induce RS related to DNA damage response (DDR) in TP53-truncated SK-N-AS cells. p53 inactivation abrogated cell cycle arrest and reduced G4 accumulation in NGP clones. The loss of p53 also induced G4 DNA helicases or Fanconi anemia group D2 protein (FANCD2) with ATRX deficiency, suggesting that ATRX maintained genome integrity and p53 deficiency attenuated RS-induced DNA damage in NB cells featuring inactivated ATRX by regulating DNA repair mechanisms and replication fork stability.
format	article
author	Jesmin Akter Yutaka Katai Parvin Sultana Hisanori Takenobu Masayuki Haruta Ryuichi P. Sugino Kyosuke Mukae Shunpei Satoh Tomoko Wada Miki Ohira Kiyohiro Ando Takehiko Kamijo
author_facet	Jesmin Akter Yutaka Katai Parvin Sultana Hisanori Takenobu Masayuki Haruta Ryuichi P. Sugino Kyosuke Mukae Shunpei Satoh Tomoko Wada Miki Ohira Kiyohiro Ando Takehiko Kamijo
author_sort	Jesmin Akter
title	Loss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma
title_short	Loss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma
title_full	Loss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma
title_fullStr	Loss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma
title_full_unstemmed	Loss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma
title_sort	loss of p53 suppresses replication stress-induced dna damage in atrx-deficient neuroblastoma
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/a2daa5a4a53642579e6bb90d160a40c5
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Loss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma

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