PD-L1 is an RNA Binding Protein That Regulates the Expression of DNA Damage Response Genes and Can be Targeted to Sensitize Cancer to Radiation

Maintenance of genome integrity is critical for both faithful propagation of genetic information and prevention of mutagenesis induced by various DNA damage events. Here we report cold-inducible RNA-binding protein (CIRBP) as a newly identified key regulator in DNA double-strand break (DSB) repair. On DNA damage, CIRBP temporarily accumulates at the damaged regions and is poly(ADP ribosyl)ated by poly(ADP ribose) polymerase-1 (PARP-1). Its dissociation from the sites of damage may depend on its phosphorylation status as mediated by phosphatidylinositol 3-kinase-related kinases. In the absence of CIRBP, cells showed reduced γH2AX, Rad51, and 53BP1 foci formation. Moreover, CIRBP-depleted cells exhibited impaired homologous recombination, impaired nonhomologous end-joining, increased micronuclei formation, and higher sensitivity to gamma irradiation, demonstrating the active involvement of CIRBP in DSB repair. Furthermore, CIRBP depleted cells exhibited defects in DNA damage-induced chromatin association of the MRN complex (Mre11, Rad50, and NBS1) and ATM kinase. CIRBP depletion also reduced phosphorylation of a variety of ATM substrate proteins and thus impaired the DNA damage response. Taken together, these results reveal a previously unrecognized role for CIRBP in DSB repair.

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A Combined Small Molecule and shRNA High-content Screen of Chromatin Modifiers Identifies an Acetyl-lysine Binding Protein as a Suppressor of the DNA Damage Response to Ionizing Radiation

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2009.07.1219 ◽

2009 ◽

Vol 75 (3) ◽

pp. S534

Author(s):

M.E. Pacold ◽

E. Blake ◽

S. Clarke ◽

A. Fydrych ◽

N. West ◽

...

Keyword(s):

Dna Damage ◽

Ionizing Radiation ◽

Dna Damage Response ◽

Small Molecule ◽

Binding Protein ◽

Damage Response ◽

Chromatin Modifiers

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INTS3 controls the hSSB1-mediated DNA damage response

The Journal of Cell Biology ◽

10.1083/jcb.200907026 ◽

2009 ◽

Vol 187 (1) ◽

pp. 25-32 ◽

Cited By ~ 54

Author(s):

Jeffrey R. Skaar ◽

Derek J. Richard ◽

Anita Saraf ◽

Alfredo Toschi ◽

Emma Bolderson ◽

...

Keyword(s):

Dna Damage ◽

Signaling Pathway ◽

Dna Damage Response ◽

Ataxia Telangiectasia ◽

Binding Protein ◽

Ataxia Telangiectasia Mutated ◽

Uncharacterized Protein ◽

Damage Response ◽

Atm Signaling Pathway ◽

Atm Signaling

Human SSB1 (single-stranded binding protein 1 [hSSB1]) was recently identified as a part of the ataxia telangiectasia mutated (ATM) signaling pathway. To investigate hSSB1 function, we performed tandem affinity purifications of hSSB1 mutants mimicking the unphosphorylated and ATM-phosphorylated states. Both hSSB1 mutants copurified a subset of Integrator complex subunits and the uncharacterized protein LOC58493/c9orf80 (henceforth minute INTS3/hSSB-associated element [MISE]). The INTS3–MISE–hSSB1 complex plays a key role in ATM activation and RAD51 recruitment to DNA damage foci during the response to genotoxic stresses. These effects on the DNA damage response are caused by the control of hSSB1 transcription via INTS3, demonstrating a new network controlling hSSB1 function.

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ATM regulates a DNA damage response posttranscriptional RNA operon in lymphocytes

Blood ◽

10.1182/blood-2010-09-310987 ◽

2011 ◽

Vol 117 (8) ◽

pp. 2441-2450 ◽

Cited By ~ 27

Author(s):

Krystyna Mazan-Mamczarz ◽

Patrick R. Hagner ◽

Yongqing Zhang ◽

Bojie Dai ◽

Elin Lehrmann ◽

...

Keyword(s):

Gene Expression ◽

Dna Damage ◽

Dna Damage Response ◽

Ataxia Telangiectasia ◽

Rna Binding ◽

Critical Role ◽

Cell Cycle Checkpoints ◽

Dependent Manner ◽

Damage Response ◽

Multiple Cell

Abstract Maintenance of genomic stability depends on the DNA damage response, a biologic barrier in early stages of cancer development. Failure of this response results in genomic instability and high predisposition toward lymphoma, as seen in patients with ataxia-telangiectasia mutated (ATM) dysfunction. ATM activates multiple cell-cycle checkpoints and DNA repair after DNA damage, but its influence on posttranscriptional gene expression has not been examined on a global level. We show that ionizing radiation modulates the dynamic association of the RNA-binding protein HuR with target mRNAs in an ATM-dependent manner, potentially coordinating the genotoxic response as an RNA operon. Pharmacologic ATM inhibition and use of ATM-null cells revealed a critical role for ATM in this process. Numerous mRNAs encoding cancer-related proteins were differentially associated with HuR depending on the functional state of ATM, in turn affecting expression of encoded proteins. The findings presented here reveal a previously unidentified role of ATM in controlling gene expression posttranscriptionally. Dysregulation of this DNA damage response RNA operon is probably relevant to lymphoma development in ataxia-telangiectasia persons. These novel RNA regulatory modules and genetic networks provide critical insight into the function of ATM in oncogenesis.

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