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

doi:10.18632/oncotarget.9914

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 journal › Article › peer-review

13 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 language	English (US)
Pages (from-to)	54430-54444
Number of pages	15
Journal	Oncotarget
Volume	7
Issue number	34
DOIs	https://doi.org/10.18632/oncotarget.9914
State	Published - 2016

Keywords

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

ASJC Scopus subject areas

Oncology

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10.18632/oncotarget.9914

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@article{9df9cede69ef41ea9671e925e0c98c8b,

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

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.",

keywords = "BER, DNA-PK, DSB repair, Ku, SAF-A/hnRNP-U",

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

note = "Funding Information: This work was supported primarily by the National Institutes of Health USPHS grant R01 CA158910 (S.M.) and in part by R01 CA NS088645 (M.L.H.), R01 GM105090 (S.M.), PO1 CA92584 (S.M. and S.P.L.M), Canadian Institute of Health MOP13639 (S.P.L.M.) and HMRI Institutional Funds (S.M. and M.L.H.). We thank Drs Tapas Hazra and Istvan Boldogh at University of Texas Medical Branch, Galveston for critical reading of the manuscript and A. Kazi at HMRI for assistance in quantitation analysis.",

year = "2016",

doi = "10.18632/oncotarget.9914",

language = "English (US)",

volume = "7",

pages = "54430--54444",

journal = "Oncotarget",

issn = "1949-2553",

publisher = "Impact Journals",

number = "34",

}

TY - JOUR

T1 - Scaffold attachment factor A (SAF-A) and Ku temporally regulate repair of radiation-induced clustered genome lesions

AU - Hegde, Muralidhar L.

AU - Dutta, Arijit

AU - Yang, Chunying

AU - Mantha, Anil K.

AU - Hegde, Pavana M.

AU - Pandey, Arvind

AU - Sengupta, Shiladitya

AU - Yu, Yaping

AU - Calsou, Patrick

AU - Chen, David

AU - Lees-Miller, Susan P.

AU - Mitra, Sankar

N1 - Funding Information: This work was supported primarily by the National Institutes of Health USPHS grant R01 CA158910 (S.M.) and in part by R01 CA NS088645 (M.L.H.), R01 GM105090 (S.M.), PO1 CA92584 (S.M. and S.P.L.M), Canadian Institute of Health MOP13639 (S.P.L.M.) and HMRI Institutional Funds (S.M. and M.L.H.). We thank Drs Tapas Hazra and Istvan Boldogh at University of Texas Medical Branch, Galveston for critical reading of the manuscript and A. Kazi at HMRI for assistance in quantitation analysis.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - BER

KW - DNA-PK

KW - DSB repair

KW - Ku

KW - SAF-A/hnRNP-U

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UR - http://www.scopus.com/inward/citedby.url?scp=84983549721&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.9914

DO - 10.18632/oncotarget.9914

M3 - Article

C2 - 27303920

AN - SCOPUS:84983549721

SN - 1949-2553

VL - 7

SP - 54430

EP - 54444

JO - Oncotarget

JF - Oncotarget

IS - 34

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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