Virus DNA Replication and the Host DNA Damage Response

Annual Review of Virology, Journal Year: 2018, Volume and Issue: 5(1), P. 141 - 164

Published: July 11, 2018

Viral DNA genomes have limited coding capacity and therefore harness cellular factors to facilitate replication of their generate progeny virions. Studies viruses how they interact with processes historically provided seminal insights into basic biology disease mechanisms. The replicative life cycles many been shown engage components the host damage repair machinery. Viruses evolved numerous strategies navigate response. By hijacking manipulating processes, can selectively or abrogate distinct machinery complete cycles. Here, we highlight consequences for viral genome integrity during dynamic interactions between virus host.

Language: Английский

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Genetic Screens Reveal FEN1 and APEX2 as BRCA2 Synthetic Lethal Targets

Molecular Cell, Journal Year: 2019, Volume and Issue: 73(5), P. 885 - 899.e6

Published: Jan. 27, 2019

Language: Английский

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ATM, ATR and DNA-PKcs kinases—the lessons from the mouse models: inhibition ≠ deletion

Cell & Bioscience, Journal Year: 2020, Volume and Issue: 10(1)

Published: Jan. 29, 2020

Abstract DNA damage, especially double strand breaks (DSBs) and replication stress, activates a complex post-translational network termed damage response (DDR). Our review focuses on three PI3-kinase related protein kinases—ATM, ATR DNA-PKcs, which situate at the apex of mammalian DDR. They are recruited to activated sites by their respective sensor complexes—MRE11/RAD50/NBS1 for ATM, RPA/ATRIP KU70–KU80/86 (XRCC6/XRCC5) DNA-PKcs. Upon activation, DNA-PKcs phosphorylate large number partially overlapping substrates promote efficient accurate repair coordinate with other metabolic events ( e.g. , transcription, mitosis). At organism level, robust DDR is critical normal development, aging, stem cell maintenance regeneration, physiological genomic rearrangements in lymphocytes germ cells. In addition endogenous oncogene-induced stresses genotoxic chemotherapies also activate On one hand, factors suppress instability prevent malignant transformation. targeting enhances therapeutic effects anti-cancer chemotherapy, led development specific kinase inhibitors Using mouse models expressing dead an unexpected structural function these kinases was revealed, where expression catalytically inactive causes more than loss proteins themselves. The spectrum instabilities consequences unique each depends activating complexes, suggesting model catalysis coupled DNA/chromatin release catalytic inhibition leads persistence lesion, turn affects pathway choice outcomes. Here we discuss experimental evidences supporting this mode action implications design use cancer therapy.

Language: Английский

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Acetylation of MORC2 by NAT10 regulates cell-cycle checkpoint control and resistance to DNA-damaging chemotherapy and radiotherapy in breast cancer

Nucleic Acids Research, Journal Year: 2020, Volume and Issue: 48(7), P. 3638 - 3656

Published: Feb. 17, 2020

MORC family CW-type zinc finger 2 (MORC2) is an oncogenic chromatin-remodeling enzyme with emerging role in DNA repair. Here, we report a novel function for MORC2 cell-cycle checkpoint control through acetylation-dependent mechanism. acetylated by the acetyltransferase NAT10 at lysine 767 (K767Ac) and this process counteracted deacetylase SIRT2 under unperturbed conditions. DNA-damaging chemotherapeutic agents ionizing radiation stimulate K767Ac enhancing interaction between NAT10. Notably, binds to histone H3 phosphorylation threonine 11 (H3T11P) essential damage-induced reduction of H3T11P transcriptional repression its downstream target genes CDK1 Cyclin B1, thus contributing G2 activation. Chemical inhibition or depletion expression acetylation-defective (K767R) forces cells pass checkpoint, resulting hypersensitivity agents. Moreover, acetylation levels are associated elevated clinical breast tumor samples. Together, these findings uncover previously unrecognized regulating NAT10-mediated provide potential therapeutic strategy sensitize cancer chemotherapy radiotherapy targeting

Language: Английский

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HLTF Promotes Fork Reversal, Limiting Replication Stress Resistance and Preventing Multiple Mechanisms of Unrestrained DNA Synthesis

Molecular Cell, Journal Year: 2020, Volume and Issue: 78(6), P. 1237 - 1251.e7

Published: May 21, 2020

Language: Английский

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