Polo-like kinase 3 regulates CtIP during DNA double-strand break repair in G1

Barton, Olivia; Naumann, Steffen C.; Diemer-Biehs, Ronja; Künzel, Julia; Steinlage, Monika; Conrad, Sandro; Makharashvili, Nodar; Wang, Jiadong; Feng, Lin; Lopez, Bernard S.; Paull, Tanya T.; Chen, Junjie; Jeggo, Penny A.; Löbrich, Markus

doi:10.1083/jcb.201401146

Cited by 96 publications

(118 citation statements)

References 70 publications

Supporting

Mentioning

114

Contrasting

Order By: Relevance

“…The S347 and S276 site are part of a group of CDK sites identified by Wang et al that promote the binding of Nbs1 to CtIP and also promote phosphorylation by ATM [40], thus, some of the modifications of CtIP are clearly essential for multiple functions. Interestingly, the non-cyclin dependent kinase Plk3 was shown to phosphorylate the S327 and T847 sites in the G 0 /G 1 cell cycle phases in response to DSBs [46], consistent with other reports suggesting roles for CtIP in G 1 [52][53][54]. However, in the absence of HR repair machinery these modifications engage CtIP and MRN into MMEJ-mediated repair [53].…”

Section: Ctip and Its Regulation In Cellsmentioning

confidence: 64%

“…Despite extensive analysis of CtIP by many groups, however, a complete understanding of how CtIP is regulated remains elusive. Cell cycle-and DNA damagedependent enzymes modify CtIP by phosphorylation, acetylation, ubiquitination, and proline isomerization, which affect protein's nuclease activity, interactions with CtIP's partner proteins, and proteasome-mediated degradation [10,[39][40][41][42][43][44][45][46].…”

Section: Ctip and Its Regulation In Cellsmentioning

confidence: 99%

“…CtIP is extensively phosphorylated by cyclin-(CDK) and DNA damage-dependent kinases, which modulate different CtIP activities [10,39,40,[44][45][46][47][48][49][50]. For example, the T847A and S327A CtIP mutants that cannot be phosphorylated by CDK are proficient in DNA binding and nuclease activity in vitro [10], but cannot complement the sensitivity of CtIP-depleted cells to DNA damaging agents, including ionizing radiation (IR), UV, cisplatin, methyl methanesulfonate (MMS), topoisomerase 1, and topoisomerase 2 poisons [39,40,48,51].…”

Section: Ctip and Its Regulation In Cellsmentioning

confidence: 99%

“…Rb-, BRCA1-, and CtBP-binding motifs are shown at a.a. 153-157, 327, and 490-494, respectively [1,3,47,68]. S/TP (green) and S/TQ (red) phosphorylation sites are depicted at S276, T315, S327, S347, T847, and S231, S664, S745, T859, respectively [10,39,40,[44][45][46]49]. K432, K526, K604 acetylation sites [41] are shown in blue.…”

mentioning

confidence: 98%

See 3 more Smart Citations

CtIP: A DNA damage response protein at the intersection of DNA metabolism

Makharashvili

Paull

2015

DNA Repair

Self Cite

View full text Add to dashboard Cite

Section: Ctip and Its Regulation In Cellsmentioning

confidence: 64%

Section: Ctip and Its Regulation In Cellsmentioning

confidence: 99%

Section: Ctip and Its Regulation In Cellsmentioning

confidence: 99%

mentioning

confidence: 98%

See 2 more Smart Citations

CtIP: A DNA damage response protein at the intersection of DNA metabolism

Makharashvili

Paull

2015

DNA Repair

Self Cite

View full text Add to dashboard Cite

“…2A). Some of these phosphorylation events have been shown to promote DNA end resection in cells (8,9,(30)(31)(32)(33)(34)(35), most notably the CDK-dependent modification of T847. In addition, ATR phosphorylation of T859 also plays an important role in CtIP binding to chromatin and CtIPmediated resection (36).…”

Section: Main Textmentioning

confidence: 99%

DNA-dependent protein kinase promotes DNA end processing by MRN and CtIP

Deshpande

Myler

Soniat

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Abstract:DNA-dependent Protein Kinase (DNA-PK) coordinates the repair of double-strand breaks through non-homologous end joining, the dominant repair pathway in mammalian cells. Breaks can also be resolved through homologous recombination during S/G 2 cell cycle phases, initiated by the Mre11-Rad50-Nbs1 (MRN) complex and CtIP-mediated resection of 5ʹ strands. The functions of DNA-PK are considered to be end-joining specific, but here we demonstrate that human DNA-PK also plays an important role in the processing of DNA double-strand breaks.Using ensemble biochemistry and single-molecule approaches, we show that the MRN complex in cooperation with CtIP is stimulated by DNA-PK to perform efficient endonucleolytic processing of DNA ends in physiological conditions. This activity requires both CDK and ATR phosphorylation of CtIP. These unexpected results could explain the absence of DNA-PK deletion mutations in the human population, as homologous recombination is an essential process in mammals.One sentence summary: An enzyme critical for non-homologous repair of DNA double-strand breaks also stimulates end processing for homologous recombination.. CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/395731 doi: bioRxiv preprint first posted online Aug. 19, 2018; 3 Main Text:DNA-dependent Protein Kinase consists of a catalytic kinase subunit (DNA-PKcs) and the DNA end-binding heterodimer of Ku70 and Ku80 (Ku). Together, these proteins form an end recognition complex (DNA-PK) that binds to DNA double-strand breaks within seconds of break formation (1). DNA-PK promotes the ligation of two DNA ends by ligase IV, aided by the accessory factors XLF, XRCC4, and APLF, and in some cases aided by limited end processing (1,2). The recognition and repair of DNA breaks by the end-joining machinery is generally considered to be the first and rapid phase of DNA repair, occurring within ~30 minutes of DNA damage, while homologous recombination is specific to the S and G 2 phases of the cell cycle and occurs over a longer time frame (3,4). DNA-PK is present at micromolar concentrations in cells (5) and binds DNA ends in all cell cycle phases, even during S phase at single-ended breaks (6). The MRN complex regulates the initiation of DNA end processing prior to homologous recombination by catalyzing the initial 5ʹ strand processing at blocked DNA ends and by recruiting long-range nucleases Exo1 and Dna2 (4, 7). At single-ended breaks during replication, the nuclease activity of Mre11 was shown to be important for removal of Ku (6), suggesting that MRN catalytic processing of ends during S phase is important for recombination-mediated repair of single-ended breaks. While we and others have shown that MRN endonuclease activity is specifically stimulated by protein blocks on DNA ends (8-11), we considered the possibility that DNA-P...

show abstract

Identification of DNA double strand breaks at chromosome boundaries along the track of particle irradiation

Niimi

Yamauchi

Limsirichaikul

et al. 2016

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Chromosomal translocations arise from misrejoining of DNA double strand breaks (DSBs) between loci located on two chromosomes. One current model suggests that spatial proximity of potential chromosomal translocation partners influences translocation probability. Ionizing radiation (IR) is a potent inducer of translocations. Accumulating evidence demonstrates that particle irradiation more frequently causes translocations compared with X-ray irradiation. This observation has led to the hypothesis that the high frequency of translocations after particle irradiation may be due to the formation of DSBs at chromosome boundaries along the particle track, because such DSBs can be misrejoined between distinct chromosomes. In this study, we simultaneously visualized the site of IR-induced DSBs and chromosome position by combining Immunofluorescence and fluorescence in situ hybridization. Importantly, the frequency of γH2AX foci at the chromosome boundary of chromosome 1 after carbon-ion irradiation was >4-fold higher than that after X-ray irradiation. This observation is consistent with the idea that particle irradiation generates DSBs at the boundaries of two chromosomes along the track. Further, we showed that resolution of γH2AX foci at chromosome boundaries is prevented by inhibition of DNA-PKcs activity, indicating that the DSB repair is NHEJ-dependent. Finally, we found that γH2AX foci at chromosome boundaries after carbon-ion irradiation contain DSBs undergoing DNA-end resection, which promotes repair utilizing microhomology mediated end-joining during translocation. Taken together, our study suggests that the frequency of DSB formation at chromosome boundaries is associated with the incidence of chromosomal translocations, supporting the notion that the spatial proximity between breaks is an important factor in translocation formation. © 2016 Wiley Periodicals, Inc.

show abstract

Polo-like kinase 3 regulates CtIP during DNA double-strand break repair in G1

Abstract: Plk3 phosphorylates CtIP in G1 in a damage-inducible manner and is required with CtIP for the repair of complex double-strand breaks and regulation of resection-mediated end-joining pathways.

Cited by 96 publications

References 70 publications

CtIP: A DNA damage response protein at the intersection of DNA metabolism

CtIP: A DNA damage response protein at the intersection of DNA metabolism

DNA-dependent protein kinase promotes DNA end processing by MRN and CtIP

Identification of DNA double strand breaks at chromosome boundaries along the track of particle irradiation

Contact Info

Product

Resources

About