The DNA repair protein NBS1 influences the base excision repair pathway

Sagan, Daniel; Müller, Romy; Kröger, Carina; Hematulin, Arunee; Mörtl, Simone; Eckardt‐Schupp, Friederike

doi:10.1093/carcin/bgp004

Cited by 12 publications

(11 citation statements)

References 46 publications

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“…One possible explanation for the lack of MMEJ activation in spite of XRCC1 phosphorylation could be the requirement of unknown IR-activated downstream factors or protein modifications, which might uniquely cause MMEJ activation. Furthermore, previous reports on NBS1's role in BER (68) could suggest formation of a discrete XRCC1–MRN complex stimulated by oxidative DNA damage with a role distinct from that in MMEJ.…”

Section: Discussionmentioning

confidence: 95%

Microhomology-mediated end joining is activated in irradiated human cells due to phosphorylation-dependent formation of the XRCC1 repair complex

et al. 2016

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Microhomology-mediated end joining (MMEJ), an error-prone pathway for DNA double-strand break (DSB) repair, is implicated in genomic rearrangement and oncogenic transformation; however, its contribution to repair of radiation-induced DSBs has not been characterized. We used recircularization of a linearized plasmid with 3΄-P-blocked termini, mimicking those at X-ray-induced strand breaks, to recapitulate DSB repair via MMEJ or nonhomologous end-joining (NHEJ). Sequence analysis of the circularized plasmids allowed measurement of relative activity of MMEJ versus NHEJ. While we predictably observed NHEJ to be the predominant pathway for DSB repair in our assay, MMEJ was significantly enhanced in preirradiated cells, independent of their radiation-induced arrest in the G2/M phase. MMEJ activation was dependent on XRCC1 phosphorylation by casein kinase 2 (CK2), enhancing XRCC1's interaction with the end resection enzymes MRE11 and CtIP. Both endonuclease and exonuclease activities of MRE11 were required for MMEJ, as has been observed for homology-directed DSB repair (HDR). Furthermore, the XRCC1 co-immunoprecipitate complex (IP) displayed MMEJ activity in vitro, which was significantly elevated after irradiation. Our studies thus suggest that radiation-mediated enhancement of MMEJ in cells surviving radiation therapy may contribute to their radioresistance and could be therapeutically targeted.

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Section: Discussionmentioning

confidence: 95%

Microhomology-mediated end joining is activated in irradiated human cells due to phosphorylation-dependent formation of the XRCC1 repair complex

et al. 2016

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“…The human cervical cancer cell line HeLa was maintained in RPMI medium 1640 (PAA Laboratories, Austria) supplemented with 10% FCS [29]. The hTERT1-immortalized human RPE cell line (Clontech Laboratories, France) was grown in D-MEM / F12 medium (Gibco BRL Life Technologies, Germany) containing 2.5 mM L-glutamine, 10% FCS, 0.25% sodium bicarbonate [30]. The human osteosarcoma cell line U2-OS (HTB-96, American Type Culture Collection (ATCC)) was grown in D-MEM medium (Invitrogen, Germany) supplemented with 2% L-glutamine (Invitrogen, Germany) and 10% FCS.…”

Section: Methodsmentioning

confidence: 99%

Cell Survival Following Radiation Exposure Requires miR-525-3p Mediated Suppression of ARRB1 and TXN1

et al. 2013

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BackgroundmicroRNAs (miRNAs) are non-coding RNAs that alter the stability and translation efficiency of messenger RNAs. Ionizing radiation (IR) induces rapid and selective changes in miRNA expression. Depletion of the miRNA processing enzymes Dicer or Ago2 reduces the capacity of cells to survive radiation exposure. Elucidation of critical radiation-regulated miRNAs and their target proteins offers a promising approach to identify new targets to increase the therapeutic effectiveness of the radiation treatment of cancer.Principal FindingsExpression of miR-525-3p is rapidly up-regulated in response to radiation. Manipulation of miR-525-3p expression in irradiated cells confirmed that this miRNA mediates the radiosensitivity of a variety of non-transformed (RPE, HUVEC) and tumor-derived cell lines (HeLa, U2-Os, EA.hy926) cell lines. Thus, anti-miR-525-3p mediated inhibition of the increase in miR-525-3p elevated radiosensitivity, while overexpression of precursor miR-525-3p conferred radioresistance. Using a proteomic approach we identified 21 radiation-regulated proteins, of which 14 were found to be candidate targets for miR-525-3p-mediated repression. Luciferase reporter assays confirmed that nine of these were indeed direct targets of miR-525-3p repression. Individual analysis of these direct targets by RNAi-mediated knockdown established that ARRB1, TXN1 and HSPA9 are essential miR-525-3p-dependent regulators of radiation sensitivity.ConclusionThe transient up-regulation of miR-525-3p, and the resultant repression of its direct targets ARRB1, TXN1 and HSPA9, is required for cell survival following irradiation. The conserved function of miR-525-3p across several cell types makes this microRNA pathway a promising target for modifying the efficacy of radiotherapy.

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“…In particular, the binding of PARP1 to the broken ends of DNA may protect it from degradation by nucleases [95]. NBS1 (Nijmegen Breakage Syndrome 1) has been recently reported to be required for base excision repair (BER) [96]. …”

Section: Introductionmentioning

confidence: 99%

Potential biological role of poly (ADP-ribose) polymerase (PARP) in male gametes

Agarwal

Mahfouz

Sharma

et al. 2009

Reprod Biol Endocrinol

112

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Maintaining the integrity of sperm DNA is vital to reproduction and male fertility. Sperm contain a number of molecules and pathways for the repair of base excision, base mismatches and DNA strand breaks. The presence of Poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme, and its homologues has recently been shown in male germ cells, specifically during stage VII of spermatogenesis. High PARP expression has been reported in mature spermatozoa and in proven fertile men. Whenever there are strand breaks in sperm DNA due to oxidative stress, chromatin remodeling or cell death, PARP is activated. However, the cleavage of PARP by caspase-3 inactivates it and inhibits PARP's DNA-repairing abilities. Therefore, cleaved PARP (cPARP) may be considered a marker of apoptosis. The presence of higher levels of cPARP in sperm of infertile men adds a new proof for the correlation between apoptosis and male infertility. This review describes the possible biological significance of PARP in mammalian cells with the focus on male reproduction. The review elaborates on the role played by PARP during spermatogenesis, sperm maturation in ejaculated spermatozoa and the potential role of PARP as new marker of sperm damage. PARP could provide new strategies to preserve fertility in cancer patients subjected to genotoxic stresses and may be a key to better male reproductive health.

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The DNA repair protein NBS1 influences the base excision repair pathway

Cited by 12 publications

References 46 publications

Microhomology-mediated end joining is activated in irradiated human cells due to phosphorylation-dependent formation of the XRCC1 repair complex

Microhomology-mediated end joining is activated in irradiated human cells due to phosphorylation-dependent formation of the XRCC1 repair complex

Cell Survival Following Radiation Exposure Requires miR-525-3p Mediated Suppression of ARRB1 and TXN1

Potential biological role of poly (ADP-ribose) polymerase (PARP) in male gametes

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