Excessive MYC-topoisome activity triggers acute DNA damage, MYC degradation, and replacement by a p53-topoisome.

Autor:	Das SK; Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA., Karmakar S; Energy Storage and Technology Department, Energy and Environment Science and Technology Division, Idaho National Laboratory, Idaho Falls, ID 83415, USA., Venkatachalapathy H; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA., Jha RK; Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA., Batchelor E; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA., Levens D; Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: levensd@mail.nih.gov.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 Nov 07; Vol. 84 (21), pp. 4059-4078.e10. Date of Electronic Publication: 2024 Oct 30.
DOI:	10.1016/j.molcel.2024.10.006
Abstrakt:	Hyperproliferation driven by the protooncogene MYC may lead to tumor suppressor p53 activating DNA damage that has been presumed to derive from hypertranscription and over-replication. Here, we report that excessive MYC-topoisome (MYC/topoisomerase 1/topoisomerase 2) activity acutely damages DNA-activating pATM and p53. In turn, MYC is shut off and degraded, releasing TOP1 and TOP2A from MYC topoisomes in vitro and in vivo. To manage the topological and torsional stress generated at its target genes, p53 assembles a separate topoisome. Because topoisomerase activity is intrinsically DNA damaging, p53 topoisomes provoke an initial burst of DNA damage. Because p53, unlike MYC, upregulates the DNA-damage response (DDR) and activates tyrosyl-DNA-phosphodiesterase (TDP) 1 and TDP2, it suppresses further topoisome-mediated damage. The physical coupling and activation of TOP1 and TOP2 by p53 creates a tool that supports p53-target expression while braking MYC-driven proliferation in mammalian cells. Competing Interests: Declaration of interests The authors declare no competing interests. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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