Cdk1 Restrains NHEJ through Phosphorylation of XRCC4-like Factor Xlf1

Hentges, Pierre; Waller, Helen Rachel; Reis, Clara C.; Ferreira, Miguel Godinho; Doherty, Aidan J.

doi:10.1016/j.celrep.2014.11.044

Cited by 22 publications

(17 citation statements)

References 22 publications

(33 reference statements)

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“…30 CDK1 activates HR by phosphorylating key recombination factors, and phosphorylates the XRCC4-like factor (XLF; also known as Cernunnos) to downregulate NHEJ, at least in yeast. 31 Repair is also linked to the cell cycle by Chk1, an effector kinase of ATR that promotes checkpoint arrest in S and G2/M, and DNA repair through RAD51 and HR. 32 Chk1 inhibition leads to DNA damage and cell death, 33 and is a potential target for improving the outcome of radiation therapy.…”

Section: Targeting Dna Damage and Repairmentioning

confidence: 99%

Opportunities and challenges of radiotherapy for treating cancer

2015

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The past 20 years have seen dramatic changes in the delivery of radiation therapy, but the impact of radiobiology on the clinic has been far less substantial. A major consideration in the use of radiotherapy has been on how best to exploit differences between the tumour and host tissue characteristics, which in the past has been achieved empirically by radiation-dose fractionation. New advances are uncovering some of the mechanistic processes that underlie this success story. In this Review, we focus on how these processes might be targeted to improve the outcome of radiotherapy at the individual patient level. This approach would seem a more productive avenue of treatment than simply trying to increase the radiation dose delivered to the tumour.

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Section: Targeting Dna Damage and Repairmentioning

confidence: 99%

Opportunities and challenges of radiotherapy for treating cancer

2015

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“…Several components of the NHEJ pathway have also been identified as targets of CDKs. However, CDK phosphorylation inhibits the recruitment of NHEJ factors, for instance, YKu70 (the yeast KU70 homolog) and Lif1 to DNA breaks in S. cerevisiae (Zhang et al, 2009) and XRCC4/XLF1 in S. pombe (Hentges et al, 2014). Thus, there appears to a reciprocal relationship between these two repair pathways where NHEJ is high in G1 and low in G2 phase, whereas HR is not possible in G1 and high in G2 phase (Ferreira & Cooper, 2004).…”

Section: Targets Of Cdk-cyc Complexes In Hr Versus Nhejmentioning

confidence: 99%

The plant‐specific CDKB 1‐ CYCB 1 complex mediates homologous recombination repair in Arabidopsis

et al. 2016

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Upon DNA damage, cyclin‐dependent kinases (CDKs) are typically inhibited to block cell division. In many organisms, however, it has been found that CDK activity is required for DNA repair, especially for homology‐dependent repair (HR), resulting in the conundrum how mitotic arrest and repair can be reconciled. Here, we show that Arabidopsis thaliana solves this dilemma by a division of labor strategy. We identify the plant‐specific B1‐type CDKs (CDKB1s) and the class of B1‐type cyclins (CYCB1s) as major regulators of HR in plants. We find that RADIATION SENSITIVE 51 (RAD51), a core mediator of HR, is a substrate of CDKB1‐CYCB1 complexes. Conversely, mutants in CDKB1 and CYCB1 fail to recruit RAD51 to damaged DNA. CYCB1;1 is specifically activated after DNA damage and we show that this activation is directly controlled by SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1), a transcription factor that acts similarly to p53 in animals. Thus, while the major mitotic cell‐cycle activity is blocked after DNA damage, CDKB1‐CYCB1 complexes are specifically activated to mediate HR.

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Section: 16mentioning

confidence: 56%

“…23 Similar to the cellular effects of our identified Akt-mediated XLF phosphorylation event in mammalian cells, Hentges et al demonstrated that phosphorylation of Xlf1 in fission yeast by Cdk1 inhibits NHEJ. 23 Hence, NHEJ can override HR when Cdk1-mediated Xlf1 phosphorylation is inhibited, arguing for a critical role of phosphorylation of XLF in suppression of NHEJ. Intrigued by the similar consequences of XLF phosphorylation events, we have aligned human XLF and fission yeast Xlf1 sequences and interestingly observed that neither the mammalian Akt site (Thr181), nor the yeast Cdk1 sites (Thr180 and Ser192) are conserved between these two species (Fig.…”

Section: 16mentioning

confidence: 56%