The dynamics of Ku70/80 and DNA-PKcs at DSBs induced by ionizing radiation is dependent on the complexity of damage

Reynolds, Pamela; Anderson, Jennifer A.; Harper, Jane V.; Hill, Mark A.; Botchway, Stanley W.; Parker, Anthony W.; O’Neill, Peter

doi:10.1093/nar/gks879

Title: The dynamics of Ku70/80 and DNA-PKcs at DSBs induced by ionizing radiation is dependent on the complexity of damage

Journal Article · Mon Sep 24 00:00:00 EDT 2012 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gks879· OSTI ID:1904541

Reynolds, Pamela ^[1]; Anderson, Jennifer A. ^[1]; Harper, Jane V. ^[1]; Hill, Mark A. ^[1]; Botchway, Stanley W. ^[2]; Parker, Anthony W. ^[2]; O’Neill, Peter ^[1]

University of Oxford (United Kingdom)
Science and Technology Facilities Council (STFC), Oxford (United Kingdom). Rutherford Appleton Lab. (RAL)

DNA double-strand breaks (DSBs) are biologically one of the most important cellular lesions and possess varying degrees of chemical complexity. The notion that the repairability of more chemically complex DSBs is inefficient led to the concept that the extent of DSB complexity underlies the severity of the biological consequences. The repair of DSBs by non-homologous end joining (NHEJ) has been extensively studied but it remains unknown whether more complex DSBs require a different sub-set of NHEJ protein for their repair compared with simple DSBs. To address this, we have induced DSBs in fluorescently tagged mammalian cells (Ku80-EGFP, DNA-PKcs-YFP or XRCC4-GFP, key proteins in NHEJ) using ultra-soft X-rays (USX) or multi-photon near infrared (NIR) laser irradiation. We have shown in real-time that simple DSBs, induced by USX or NIR microbeam irradiation, are repaired rapidly involving Ku70/80 and XRCC4/Ligase IV/XLF. In contrast, DSBs with greater chemical complexity are repaired slowly involving not only Ku70/80 and XRCC4/Ligase IV/XLF but also DNA-PKcs. Ataxia telangiectasiamutated inhibition only retards repair of the more chemically complex DSBs which require DNA-PKcs. In summary, the repair of DSBs by NHEJ is highly regulated with pathway choice and kinetics of repair dependent on the chemical complexity of the DSB.

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Research Organization:: Univ. of Oxford (United Kingdom)

Sponsoring Organization:: USDOE Office of Science (SC); Science and Technology Facilities Council Biomed Network; Medical Research Council

Grant/Contract Number:: SC0002296; HNB3003; 89975

OSTI ID:: 1904541

Journal Information:: Nucleic Acids Research, Vol. 40, Issue 21; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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