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Modeling the interplay between DNA-PK, Artemis, and ATM in non-homologous end-joining repair in G1 phase of the cell cycle

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Abstract

Modeling a biological process equips us with more comprehensive insight into the process and a more advantageous experimental design. Non-homologous end joining (NHEJ) is a major double-strand break (DSB) repair pathway that occurs throughout the cell cycle. The objective of the current work is to model the fast and slow phases of NHEJ in G1 phase of the cell cycle following exposure to ionizing radiation (IR). The fast phase contains the major components of NHEJ; Ku70/80 complex, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and XLF/XRCC4/ligase IV complex (XXL). The slow phase in G1 phase of the cell cycle is associated with more complex lesions and involves ATM and Artemis proteins in addition to the major components. Parameters are mainly obtained from experimental data. The model is successful in predicting the kinetics of DSB foci in 13 normal, ATM-deficient, and Artemis-deficient mammalian fibroblast cell lines in G1 phase of the cell cycle after exposure to low doses of IR. The involvement of ATM provides the model with the potency to be connected to different signaling pathways. Ku70/80 concentration and DNA-binding rate as well as XXL concentration and enzymatic activity are introduced as the best targets for affecting NHEJ DSB repair process. On the basis of the current model, decreasing concentration and DNA binding rate of DNA-PKcs is more effective than inhibiting its activity towards the Artemis protein.

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Abbreviations

ATM:

Ataxia telangiectasia mutated

CC:

Correlation coefficient

DNA-PKcs:

DNA-dependent protein kinase catalytic subunit

DSB:

Double-strand break

HR:

Homologous recombination

IR:

Ionizing radiation

Ku:

Ku70/80 complex

MEF:

Mouse embryonic fibroblast

NHEJ:

Non-homologous end joining

PIKK:

Phosphatidylinositol 3-kinase-related kinase

XLF:

XRCC4-like factor

XXL:

XLF/XRCC4/ligase IV complex

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The Institute for Advanced Studies in Basic Sciences (IASBS) is acknowledged for supporting this work.

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  1. Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan, 45137-66731, Iran

    Maryam Rouhani

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Rouhani, M. Modeling the interplay between DNA-PK, Artemis, and ATM in non-homologous end-joining repair in G1 phase of the cell cycle. J Biol Phys 45, 127–146 (2019). https://doi.org/10.1007/s10867-018-9519-2

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