An Intrinsically Disordered APLF Links Ku, DNA-PKcs, and XRCC4-DNA Ligase IV in an Extended Flexible Non-homologous End Joining Complex

Hammel, Michal; Yu, Yaping; Radhakrishnan, Sarvan K.; Chokshi, Chirayu; Tsai, Miaw-Sheue; Matsumoto, Yoshihiro; Kuzdovich, Monica; Remesh, Soumya G.; Fang, Shujuan; Tomkinson, Alan E.; Lees-Miller, Susan P.; Tainer, John A.

doi:10.1074/jbc.M116.751867

Title: An Intrinsically Disordered APLF Links Ku, DNA-PKcs, and XRCC4-DNA Ligase IV in an Extended Flexible Non-homologous End Joining Complex

Journal Article · Thu Dec 01 00:00:00 EST 2016 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M116.751867· OSTI ID:1769194

Hammel, Michal; Yu, Yaping; Radhakrishnan, Sarvan K.; Chokshi, Chirayu; Tsai, Miaw-Sheue; Matsumoto, Yoshihiro; Kuzdovich, Monica; Remesh, Soumya G.; Fang, Shujuan; Tomkinson, Alan E.; Lees-Miller, Susan P.; Tainer, John A.

DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) in human cells is initiated by Ku heterodimer binding to a DSB, followed by recruitment of core NHEJ factors including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4-like factor (XLF), and XRCC4 (X4)-DNA ligase IV (L4). Ku also interacts with accessory factors such as aprataxin and polynucleotide kinase/phosphatase-like factor (APLF). But, how these factors interact to tether, process, and ligate DSB ends while allowing regulation and chromatin interactions remains enigmatic. Here, small angle X-ray scattering (SAXS) and mutational analyses show APLF is largely an intrinsically disordered protein that binds Ku, Ku/DNA-PKcs (DNA-PK), and X4L4 within an extended flexible NHEJ core complex. X4L4 assembles with Ku heterodimers linked to DNA-PKcs via flexible Ku80 C-terminal regions (Ku80CTR) in a complex stabilized through APLF interactions with Ku, DNA-PK, and X4L4. Our collective results unveil the solution architecture of the six-protein complex and suggest cooperative assembly of an extended flexible NHEJ core complex that supports APLF accessibility while possibly providing flexible attachment of the core complex to chromatin. The resulting dynamic tethering furthermore, provides geometric access of L4 catalytic domains to the DNA ends during ligation and of DNA-PKcs for targeted phosphorylation of other NHEJ proteins as well as trans-phosphorylation of DNA-PKcs on the opposing DSB without disrupting the core ligation complex. Overall the results shed light on evolutionary conservation of Ku, X4, and L4 activities, while explaining the observation that Ku80CTR and DNA-PKcs only occur in a subset of higher eukaryotes.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: IDAT; AC02-05CH11231

OSTI ID:: 1769194

Alternate ID(s):: OSTI ID: 1379623

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Vol. 291 Journal Issue: 53; ISSN 0021-9258

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 45 works

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
DNA repair
DNA-dependent serine/threonine protein kinase (DNA-PK)
intrinsically disordered protein
protein complex
small-angle x-ray scattering (SAXS)
APLF
DNA ligase IV
Ku
XRCC4
non-homologous end joining

Title: An Intrinsically Disordered APLF Links Ku, DNA-PKcs, and XRCC4-DNA Ligase IV in an Extended Flexible Non-homologous End Joining Complex

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