Homology-directed repair protects the replicating genome from metabolic assaults

Item Type:	Article
Title:	Homology-directed repair protects the replicating genome from metabolic assaults
Creators Name:	Somyajit, K. and Spies, J. and Coscia, F. and Kirik, U. and Rask, M.B. and Lee, J.H. and Neelsen, K.J. and Mund, A. and Jensen, L.J. and Paull, T.T. and Mann, M. and Lukas, J.
Abstract:	Homology-directed repair (HDR) safeguards DNA integrity under various forms of stress, but how HDR protects replicating genomes under extensive metabolic alterations remains unclear. Here, we report that besides stalling replication forks, inhibition of ribonucleotide reductase (RNR) triggers metabolic imbalance manifested by the accumulation of increased reactive oxygen species (ROS) in cell nuclei. This leads to a redox-sensitive activation of the ATM kinase followed by phosphorylation of the MRE11 nuclease, which in HDR-deficient settings degrades stalled replication forks. Intriguingly, nascent DNA degradation by the ROS-ATM-MRE11 cascade is also triggered by hypoxia, which elevates signaling-competent ROS and attenuates functional HDR without arresting replication forks. Under these conditions, MRE11 degrades daughter-strand DNA gaps, which accumulate behind active replisomes and attract error-prone DNA polymerases to escalate mutation rates. Thus, HDR safeguards replicating genomes against metabolic assaults by restraining mutagenic repair at aberrantly processed nascent DNA. These findings have implications for cancer evolution and tumor therapy.
Keywords:	Homology-Directed Repair, Ribonucleotide Reductase, Hypoxia, Reactive Oxygen Species, Nascent DNA Degradation, Translesion DNA Synthesis, Cancer Evolution, BRCA1/2, Replication Stress, Genome Instability
Source:	Developmental Cell
ISSN:	1534-5807
Publisher:	Cell Press
Volume:	56
Number:	4
Page Range:	461-477
Date:	22 February 2021
Official Publication:	https://doi.org/10.1016/j.devcel.2021.01.011
PubMed:	View item in PubMed

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