Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation

  title={Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation},
  author={Junya Kobayashi and Akihiro Kato and Yosuke Ota and Reiko Ohba and Kenshi Komatsu},
  journal={Molecular Cancer},
  pages={34 - 34}
BackgroundMRE11 is an important nuclease which functions in the end-resection step of homologous recombination (HR) repair of DNA double-strand breaks (DSBs). As MRE11-deficient ATLD cells exhibit hyper radio-sensitivity and impaired DSB repair, MRE11 inhibitors could possibly function as potent radio-sensitizers. Therefore, we investigated whether a bisbenzamidine derivative, pentamidine, which can inhibit endoexonuclease activity, might influence DSB-induced damage responses via inhibition of… 
Nucleolin Participates in DNA Double-Strand Break-Induced Damage Response through MDC1-Dependent Pathway
Nucleolin-knockdown decreased MDC1-related events such as focus formation of 53 BP1, RNF168, phosphorylated ATM, and H2A ubiquitination and showed FACT-like activity for DSB damage-induced histone eviction from chromatin, taken together.
Chromatin modification and NBS1: their relationship in DNA double-strand break repair.
Information about the roles of such chromatin modifications and NBS1 in non-homologous end joining (NHEJ) repair of DSBs and stalled fork-related damage responses is very limited and these aspects and processes need to be further studied to advance the understanding of the mechanisms and molecular players involved.
Schizosaccharomyces pombe KAT5 contributes to resection and repair of a DNA double strand break
The data suggest that Mst1 functions to direct repair of DSBs towards homologous recombination pathways by modulating resection at the double strand break.
NBS1 is regulated by two kind of mechanisms: ATM-dependent complex formation with MRE11 and RAD50, and cell cycle–dependent degradation of protein
Investigation of the regulatory mechanisms of MRN complex formation suggests that NBS1 is regulated by two kind of mechanisms: complex formation dependent on ATM, and protein degradation mediated by an unknown MG132-resistant pathway that may contribute to cellular responses to double-strand breaks.
Relative contribution of four nucleases, CtIP, Dna2, Exo1 and Mre11, to the initial step of DNA double‐strand break repair by homologous recombination in both the chicken DT40 and human TK6 cell lines
It is suggested that Mre11 is involved in a mechanism other than DSB resection, during which DSBs are processed by nucleases to generate 3′ single‐strand DNA, to ensure efficient DSB repair by HR.
Activation of the SUMO modification system is required for the accumulation of RAD51 at sites of DNA damage
It is shown that the SUMOylation E2 ligase UBC9, and E3 ligases PIAS1 and PIAS4, are required for RAD51 accretion at sites containing DNA damage in human cells, and the identified a SUMO-interacting motif (SIM) in RAD51, which is necessary for accumulation of RAD51 at sites of DNA damage.
Regulation of homologous recombinational repair by lamin B1 in radiation‐induced DNA damage
  • Ning Liu, Jiying Sun, S. Tashiro
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2015
It is proposed that lamin B1 promotes DSB repair and cell survival by maintaining the RAD51 protein levels for HR upon DSB induction after IR upon radiation‐induced DNA damage.
Chronic treatment with cisplatin induces chemoresistance through the TIP60-mediated Fanconi anemia and homologous recombination repair pathways
It is found that the chemoresistant nasopharyngeal carcinoma cells, derived from chronic treatment of cisplatin, show elevated expression of TIP60 and the depletion of Tip60 significantly reduces sister chromatid exchange, a measurement of HR efficiency.
Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks
The results firmly establish that mutation of the MTPAP gene results in a cellular phenotype of increased DNA damage, reduced repair kinetics, increased cell death by apoptosis, and reduced clonogenic survival after exposure to ionizing radiation, suggesting a pathogenesis that involves the disruption of ROS homeostasis.


Histone H2AX participates the DNA damage-induced ATM activation through interaction with NBS1.
Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex.
It is shown that the triple complex of recombinant Nbs1, Mre11, and Rad50 proteins binds cooperatively to DNA and forms a distinct protein-DNA species.
MDC1 is a mediator of the mammalian DNA damage checkpoint
It is shown by using small interfering RNA that cells lacking MDC1 are sensitive to ionizing radiation, and that M DC1 controls the formation of damage-induced 53BP1, BRCA1 and MRN foci, in part by promoting efficient H2AX phosphorylation.
The DNA double-stranded break repair protein endo-exonuclease as a therapeutic target for cancer.
Pentamidine synergistically potentiates the cytotoxic effect of DNA strand break and cross-link-inducing agents such as mitomycin C, etoposide, and cisplatin and is an inhibitor of the endo-exonuclease as determined by enzyme kinetic assay.
NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain.
NBS1, the gene product defective in Nijmegen breakage syndrome (NBS), physically interacts with histone, rather than damaged DNA, by direct binding to gamma-H2AX, and the FHA/BRCT domain of NBS1 is essential for this physical interaction.
NBS1 Localizes to γ-H2AX Foci through Interaction with the FHA/BRCT Domain
Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells
The disruption of Nbs1 reduces gene conversion and sister chromatid exchanges, similar to other HR-deficient mutants, and a site-specific double-strand break repair assay showed a notable reduction of HR events following generation of such breaks in NBS1-disrupted cells.
Homologous recombination repair is regulated by domains at the N- and C-terminus of NBS1 and is dissociated with ATM functions
The results suggested that the N- and C-terminal domains of NBS1 are the major regulatory domains for HR pathways, very likely through the recruitment and retention of the MRE11 nuclease to DSB sites in an ATM-independent fashion.
Dancing on damaged chromatin: functions of ATM and the RAD50/MRE11/NBS1 complex in cellular responses to DNA damage.
The focus is on the role of ATM and the RAD50/MRE11/NBS1 complex in DSB response pathways, and their role in D SB repair and in the regulation of chromatin remodeling.