Scaffold attachment factor A (SAF-A) and Ku temporally regulate repair of radiation-induced clustered genome lesions

Muralidhar L. Hegde, Arijit Dutta, Chunying Yang, Anil K. Mantha, Pavana M. Hegde, Arvind Pandey, Shiladitya Sengupta, Yaping Yu, Patrick Calsou, David Chen, Susan P. Lees-Miller, Sankar Mitra

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Ionizing radiation (IR) induces highly cytotoxic double-strand breaks (DSBs) and also clustered oxidized bases in mammalian genomes. Base excision repair (BER) of bi-stranded oxidized bases could generate additional DSBs as repair intermediates in the vicinity of direct DSBs, leading to loss of DNA fragments. This could be avoided if DSB repair via DNA-PK-mediated nonhomologous end joining (NHEJ) precedes BER initiated by NEIL1 and other DNA glycosylases (DGs). Here we show that DNAPK subunit Ku inhibits DGs via direct interaction. The scaffold attachment factor (SAF)-A, (also called hnRNP-U), phosphorylated at Ser59 by DNA-PK early after IR treatment, is linked to transient release of chromatin-bound NEIL1, thus preventing BER. SAF-A is subsequently dephosphorylated. Ku inhibition of DGs in vitro is relieved by unphosphorylated SAF-A, but not by the phosphomimetic Asp59 mutant. We thus propose that SAF-A, in concert with Ku, temporally regulates base damage repair in irradiated cell genome.

Original languageEnglish (US)
Pages (from-to)54430-54444
Number of pages15
JournalOncotarget
Volume7
Issue number34
DOIs
StatePublished - 2016

Keywords

  • BER
  • DNA-PK
  • DSB repair
  • Ku
  • SAF-A/hnRNP-U

ASJC Scopus subject areas

  • Oncology

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    Hegde, M. L., Dutta, A., Yang, C., Mantha, A. K., Hegde, P. M., Pandey, A., Sengupta, S., Yu, Y., Calsou, P., Chen, D., Lees-Miller, S. P., & Mitra, S. (2016). Scaffold attachment factor A (SAF-A) and Ku temporally regulate repair of radiation-induced clustered genome lesions. Oncotarget, 7(34), 54430-54444. https://doi.org/10.18632/oncotarget.9914