PARP-1–dependent recruitment of cold-inducible RNA-binding protein promotes double-strand break repair and genome stability

Abstract

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.

The Enigmatic Function of PARP1: From PARylation Activity to PAR Readers

“…PARylation mutant of all these residues in CIRBP blocks pS1981-ATM association with chromatin, but not phosphorylation level of ATM [99]. A similar effect has been observed for NBS1 and MRE11 accumulation on chromatin [99]. Thus, PARylated CIRBP can interact with ATM and the MRN complex to facilitate their binding to chromatin at the lesions.…”

“…CIRBP is recruited to the DNA damage site and binds already existing PAR moieties, provided by autoPARylated PARP1, via its C-terminal RGG-rich motif-likely helped by its N-terminal RNA-recognition motif (RRM) [99]. PARylation mutant of all these residues in CIRBP blocks pS1981-ATM association with chromatin, but not phosphorylation level of ATM [99]. A similar effect has been observed for NBS1 and MRE11 accumulation on chromatin [99].…”

“…The cold-inducible RNA-binding protein (CIRBP) binds to 3 -UTR of stress-responsive and circadian clock RNAs and is found to participate in DSB repair via PAR-binding [99]. CIRBP is recruited to the DNA damage site and binds already existing PAR moieties, provided by autoPARylated PARP1, via its C-terminal RGG-rich motif-likely helped by its N-terminal RNA-recognition motif (RRM) [99]. PARylation mutant of all these residues in CIRBP blocks pS1981-ATM association with chromatin, but not phosphorylation level of ATM [99].…”

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

“…[168][169][170][171][172][173][174][175][176][177] Additionally, PARPs and sirtuins also simulate genomic damage-signaling kinases, including ATM, p53, DNA-PK, CIRBP and FOXOs, to accelerate DNA repair. [178][179][180][181][182] Given that DNA damage-activated PARPs account for up to 90% of cellular NAD + consumption, the DNA repair activity is highly dependent on the cellular NAD + concentration. 133,183,184 As expected, decreased NAD + levels induce the accumulation of DNA damage, whereas replenishing intracellular NAD + stimulates the DNA repair.…”

Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

“…One of the major functions of PARP1 is to repair DNA single-strand breaks (SSBs) through base excision repair (BER) [59]. Meanwhile, PARP1 also plays an indispensable role in DSB repair pathways, including HR and NHEJ [60]. Inhibition of PARP in BRCA1/2-deficient breast cancer cells leads to "synthetic lethality".…”