APLF (C2orf13) facilitates nonhomologous end-joining and undergoes ATM-dependent hyperphosphorylation following ionizing radiation

Macrae, Chloe J.; McCulloch, Richard; Ylanko, Jarkko; Durocher, Daniel; Koch, Christine

doi:10.1016/j.dnarep.2007.10.008

Cited by 87 publications

(124 citation statements)

References 37 publications

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“…APLF is comprised of highly conserved amino-and carboxylterminal domains separated by a relatively nonconserved central region and was recently identified as a novel component of DNA SSBR and DSBR (4,14,15,19). The amino-terminal domain encodes an FHA domain that interacts with CK2-phosphorylated XRCC1 and XRCC4 and facilitates the accumulation of APLF at sites of chromosomal DNA damage in an XRCC1-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we and others identified the human protein APLF (aka C2orf13, PALF, and XIP1) as a novel component of the DNA single-strand break repair (SSBR) and double-strand break repair (DSBR) machinery (4,14,15,19). The amino terminus of APLF contains a highly conserved forkhead-associated (FHA) domain that mediates interaction with the SSBR and DSBR factors XRCC1 and XRCC4, respectively.…”

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confidence: 99%

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APLF (C2orf13) Is a Novel Component of Poly(ADP-Ribose) Signaling in Mammalian Cells

Rulten

Cortés‐Ledesma

Guo

et al. 2008

Molecular and Cellular Biology

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APLF is a novel protein of unknown function that accumulates at sites of chromosomal DNA strand breakage via forkhead-associated (FHA) domain-mediated interactions with XRCC1 and XRCC4. APLF can also accumulate at sites of chromosomal DNA strand breaks independently of the FHA domain via an unidentified mechanism that requires a highly conserved C-terminal tandem zinc finger domain. Here, we show that the zinc finger domain binds tightly to poly(ADP-ribose), a polymeric posttranslational modification synthesized transiently at sites of chromosomal damage to accelerate DNA strand break repair reactions. Protein poly(ADP-ribosyl)ation is tightly regulated and defects in either its synthesis or degradation slow global rates of chromosomal single-strand break repair. Interestingly, APLF negatively affects poly(ADPribosyl)ation in vitro, and this activity is dependent on its capacity to bind the polymer. In addition, transient overexpression in human A549 cells of full-length APLF or a C-terminal fragment encoding the tandem zinc finger domain greatly suppresses the appearance of poly(ADP-ribose), in a zinc finger-dependent manner. We conclude that APLF can accumulate at sites of chromosomal damage via zinc finger-mediated binding to poly(ADP-ribose) and is a novel component of poly(ADP-ribose) signaling in mammalian cells.The rapid repair of chromosomal DNA single-and doublestrand breaks is critical for genome integrity, and defects in this process result in a variety of hereditary genetic diseases (21). Recently, we and others identified the human protein APLF (aka C2orf13, PALF, and XIP1) as a novel component of the DNA single-strand break repair (SSBR) and double-strand break repair (DSBR) machinery (4,14,15,19). The amino terminus of APLF contains a highly conserved forkhead-associated (FHA) domain that mediates interaction with the SSBR and DSBR factors XRCC1 and XRCC4, respectively. In addition, APLF interacts with Ku80 in an FHA domain-independent manner. The C terminus of APLF contains a second highly conserved region that encodes two tandem zinc fingers (designated ZNF1 and ZNF2) and a highly acidic tail. Both the FHA domain and the tandem ZNFs can facilitate, by independent mechanisms, the accumulation of APLF at sites of DNA strand breakage (4,14,15). Whereas the FHA domain facilitates APLF accumulation via interaction with CK2-phosphorylated XRCC1, the mechanism by which the ZNFs achieve this is unclear.The ZNFs in APLF most closely resemble the tandem zinc fingers present in tristetraprolin. Tristetraprolin binds specific mRNA species, with each of two ZNFs targeting a separate 5Ј-UAUU-3Ј subsite located within a larger, AU-rich recognition sequence (5, 18). Although APLF does not bind this mRNA species (unpublished observations), it is possible that the APLF ZNFs might interact with some other type of adenine-rich structure. One such structure that arises during DNA strand break repair is poly(ADP-ribose) (pADPr), a branched nucleic acid-like polymer synthesized rapidly at DNA strand breaks by pADPr po...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

APLF (C2orf13) Is a Novel Component of Poly(ADP-Ribose) Signaling in Mammalian Cells

Rulten

Cortés‐Ledesma

Guo

et al. 2008

Molecular and Cellular Biology

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“…APLF is an important constituent of the non-homologous end joining (NHEJ)-mediated DNA damage repair machinery (Rulten et al, 2008;Grundy et al, 2013), and its downregulation in human cells could sensitize the cells to various DNA-damaging agents (Macrae et al, 2008). In order to test whether Aplf knockdown induces DNA repair defects, the cells were first challenged with actinomycin D at different concentrations and subjected to an apoptosis assay.…”

Section: Downregulation Of Aplf Enhances Reprogramming Of Fibroblastsmentioning

confidence: 99%

Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts

Syed

Joseph

Mukherjee³

et al. 2016

Journal of Cell Science

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The authors apologise to the readers for any confusion that this error might have caused. For the first time, we report here that the downregulation of histone chaperone Aprataxin PNK-like factor (APLF) promotes reprogramming by augmenting the expression of E-cadherin (Cdh1), which is implicated in the mesenchymal-to-epithelial transition (MET) involved in the generation of induced pluripotent stem cells (iPSCs) from mouse embryonic fibroblasts (MEFs). Downregulation of APLF in MEFs expedites the loss of the repressive MacroH2A.1 (encoded by H2afy) histone variant from the Cdh1 promoter and enhances the incorporation of active histone H3me2K4 marks at the promoters of the pluripotency genes Nanog and Klf4, thereby accelerating the process of cellular reprogramming and increasing the efficiency of iPSC generation. We demonstrate a new histone chaperone (APLF)-MET-histone modification cohort that functions in the induction of pluripotency in fibroblasts. This regulatory axis might provide new mechanistic insights into perspectives of epigenetic regulation involved in cancer metastasis.

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“…Pretreatment with 10 M anisomycin was performed for 20 min at 37°C. -Protein phosphatase treatments were performed as previously described (19). For immunoprecipitations, clarified WCEs were incubated with 1 g of the relevant antibody on ice for 60 min with occasional gentle agitation, followed by the addition of 30 l of protein A-coupled Sepharose beads (ThermoFisher) and incubated for an additional 1 h at 4°C, or WCEs were incubated with V5-agarose (Sigma) at 4°C for 2 h. Immunoprecipitates were washed three times with lysis buffer, resuspended in SDS-PAGE sample buffer, and resolved by SDS-PAGE.…”

Section: Methodsmentioning

confidence: 99%

Differential Regulation of Mitogen- and Stress-activated Protein Kinase-1 and -2 (MSK1 and MSK2) by CK2 following UV Radiation

Jacks

Koch

2010

Journal of Biological Chemistry

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APLF (C2orf13) facilitates nonhomologous end-joining and undergoes ATM-dependent hyperphosphorylation following ionizing radiation

Cited by 87 publications

References 37 publications

APLF (C2orf13) Is a Novel Component of Poly(ADP-Ribose) Signaling in Mammalian Cells

APLF (C2orf13) Is a Novel Component of Poly(ADP-Ribose) Signaling in Mammalian Cells

Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts

Differential Regulation of Mitogen- and Stress-activated Protein Kinase-1 and -2 (MSK1 and MSK2) by CK2 following UV Radiation

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