An in vivo Interaction Network of DNA-Repair Proteins: A Snapshot at Double Strand Break Repair in Deinococcus radiodurans

Abstract The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. ATM mutant cells exhibit impaired DNA double strand break repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. We investigated in vitro sensitivity to the poly (ADP-ribose) polymerase inhibitor olaparib (AZD2281) of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line, and 9 ATM-deficient primary CLLs induced to cycle and observed differential killing compared with ATM wildtype counterparts. Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. A nonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo. Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.

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Double‐strand break repair based on short‐homology regions is suppressed under terminal deoxynucleotidyltransferase expression, as revealed by a novel vector system for analysing DNA repair by nonhomologous end joining

FEBS Open Bio ◽

10.1002/2211-5463.12001 ◽

2016 ◽

Vol 6 (1) ◽

pp. 16-23 ◽

Cited By ~ 2

Author(s):

So Maezawa ◽

Saori Nakano ◽

Takaaki Kuniya ◽

Osamu Koiwai ◽

Kotaro Koiwai

Keyword(s):

Dna Repair ◽

Strand Break ◽

Double Strand Break ◽

Nonhomologous End Joining ◽

Double Strand Break Repair ◽

Vector System ◽

End Joining ◽

Break Repair

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“Polymorphisms in double strand break repair related genes influence radiosensitivity phenotype in lymphocytes from healthy individuals” [DNA Repair 40 (2016) 27–34]

DNA Repair ◽

10.1016/j.dnarep.2016.05.028 ◽

2016 ◽

Vol 43 ◽

pp. 113

Author(s):

Kamalesh Dattaram Mumbrekar ◽

Hassan Venkatesh Goutham ◽

Bejadi Manjunath Vadhiraja ◽

Satish Rao Bola Sadashiva

Keyword(s):

Dna Repair ◽

Strand Break ◽

Double Strand Break ◽

Double Strand Break Repair ◽

Healthy Individuals ◽

Break Repair

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Ubiquitylation-Mediated Fine-Tuning of DNA Double-Strand Break Repair

Cancers ◽

10.3390/cancers12061617 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1617

Author(s):

Barbara N. Borsos ◽

Hajnalka Majoros ◽

Tibor Pankotai

Keyword(s):

Dna Repair ◽

Strand Break ◽

Double Strand Break ◽

Fine Tuning ◽

Double Strand Break Repair ◽

Proper Function ◽

Dna Damages ◽

Regulatory Pathways ◽

Dna Double Strand Break ◽

Break Repair

The proper function of DNA repair is indispensable for eukaryotic cells since accumulation of DNA damages leads to genome instability and is a major cause of oncogenesis. Ubiquitylation and deubiquitylation play a pivotal role in the precise regulation of DNA repair pathways by coordinating the recruitment and removal of repair proteins at the damaged site. Here, we summarize the most important post-translational modifications (PTMs) involved in DNA double-strand break repair. Although we highlight the most relevant PTMs, we focus principally on ubiquitylation-related processes since these are the most robust regulatory pathways among those of DNA repair.

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Molecular Characterization of the Role of the Schizosaccharomyces pombe nip1+/ctp1+ Gene in DNA Double-Strand Break Repair in Association with the Mre11-Rad50-Nbs1 Complex

Molecular and Cellular Biology ◽

10.1128/mcb.01828-07 ◽

2008 ◽

Vol 28 (11) ◽

pp. 3639-3651 ◽

Cited By ~ 38

Author(s):

Yufuko Akamatsu ◽

Yasuto Murayama ◽

Takatomi Yamada ◽

Tomofumi Nakazaki ◽

Yasuhiro Tsutsui ◽

...

Keyword(s):

Dna Repair ◽

Schizosaccharomyces Pombe ◽

Sequence Similarity ◽

Strand Break ◽

Double Strand Break ◽

Double Strand Break Repair ◽

Dna Double Strand Breaks ◽

Epistasis Analysis ◽

Dna Double Strand Break ◽

Break Repair

ABSTRACT The Schizosaccharomyces pombe nip1 +/ctp1 + gene was previously identified as an slr (synthetically lethal with rad2) mutant. Epistasis analysis indicated that Nip1/Ctp1 functions in Rhp51-dependent recombinational repair, together with the Rad32 (spMre11)-Rad50-Nbs1 complex, which plays important roles in the early steps of DNA double-strand break repair. Nip1/Ctp1 was phosphorylated in asynchronous, exponentially growing cells and further phosphorylated in response to bleomycin treatment. Overproduction of Nip1/Ctp1 suppressed the DNA repair defect of an nbs1-s10 mutant, which carries a mutation in the FHA phosphopeptide-binding domain of Nbs1, but not of an nbs1 null mutant. Meiotic DNA double-strand breaks accumulated in the nip1/ctp1 mutant. The DNA repair phenotypes and epistasis relationships of nip1/ctp1 are very similar to those of the Saccharomyces cerevisiae sae2/com1 mutant, suggesting that Nip1/Ctp1 is a functional homologue of Sae2/Com1, although the sequence similarity between the proteins is limited to the C-terminal region containing the RHR motif. We found that the RxxL and CxxC motifs are conserved in Schizosaccharomyces species and in vertebrate CtIP, originally identified as a cofactor of the transcriptional corepressor CtBP. However, these two motifs are not found in other fungi, including Saccharomyces and Aspergillus species. We propose that Nip1/Ctp1 is a functional counterpart of Sae2/Com1 and CtIP.

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