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Identifying novel targets for molecular radiosensitization is critical to improve the efficacy of cancer radiotherapy. Alpha-thalassemia/mental retardation X-linked (ATRX), a member of the SWI/SNF-like chromatin remodeling protein family, functions in the maintenance of genomic integrity, alternative lengthening of telomeres, and the regulation of apoptosis and senescence. However, whether ATRX is directly involved in the DNA damage response (DDR) remains unknown. Here, we show that silencing ATRX increased the sensitivity of cells to ionizing radiation (IR). IR-induced DNA damage was greater and G2/M arrest was less efficient in ATRX knockdown cells. ATRX downregulation caused defects in apoptosis and senescence, indicating that ATRX has a biological function in the DDR. ATRX loss led to failure to trigger ataxia telangiectasia-mutated (ATM) auto-phosphorylation, inhibiting the activation of ATM/Chk2 downstream effectors. These data identify ATRX as a novel target for radiosensitization, and its effect depends on inhibition of the ATM/Chk2 pathway in the DDR.
Keywords
Ionizing radiation, ATRX, ATM, DNA damage repair, cycle arrest
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 21 Aug, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Identifying novel targets for molecular radiosensitization is critical to improve the efficacy of cancer radiotherapy. Alpha-thalassemia/mental retardation X-linked (ATRX), a member of the SWI/SNF-like chromatin remodeling protein family, functions in the maintenance of genomic integrity, alternative lengthening of telomeres, and the regulation of apoptosis and senescence. However, whether ATRX is directly involved in the DNA damage response (DDR) remains unknown. Here, we show that silencing ATRX increased the sensitivity of cells to ionizing radiation (IR). IR-induced DNA damage was greater and G2/M arrest was less efficient in ATRX knockdown cells. ATRX downregulation caused defects in apoptosis and senescence, indicating that ATRX has a biological function in the DDR. ATRX loss led to failure to trigger ataxia telangiectasia-mutated (ATM) auto-phosphorylation, inhibiting the activation of ATM/Chk2 downstream effectors. These data identify ATRX as a novel target for radiosensitization, and its effect depends on inhibition of the ATM/Chk2 pathway in the DDR.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
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