Affinage

APLF

Aprataxin and PNK-like factor · UniProt Q8IW19

Length
511 aa
Mass
57.0 kDa
Annotated
2026-04-28
28 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

APLF is a multifunctional scaffold protein in the non-homologous end-joining (NHEJ) pathway of DNA double-strand break repair, integrating damage recognition, chromatin remodeling, and ligation complex assembly. APLF is recruited to DNA lesions through dual mechanisms: its FHA domain binds CK2-phosphorylated XRCC1 and XRCC4, while its tandem PBZ zinc finger domains recognize poly(ADP-ribose) chains synthesized by PARP-1 and PARP-3 (PMID:17353262, PMID:18474613, PMID:21211721). Once at damage sites, APLF binds the Ku80 vWA domain via a conserved Ku-binding motif and acts as a scaffold that promotes retention of XRCC4–DNA ligase IV and XLF, stabilizes DNA end synapsis, and enables efficient ligation (PMID:23178593, PMID:30291363, PMID:36640344). Its intrinsically disordered acidic domain functions as a histone chaperone that binds H3–H4 and H2A–H2B, assembles intact histone octamers, and deposits them onto DNA to form nucleosomes, coupling chromatin restoration to DNA repair (PMID:21211722, PMID:35895815).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2007 High

    The first studies identified APLF as a DNA damage-responsive factor recruited to strand breaks through two independent mechanisms — FHA domain interaction with CK2-phosphorylated XRCC1 and a zinc finger-dependent pathway — establishing it as a participant in single- and double-strand break repair.

    Evidence YFP/GFP-tagged recruitment at laser-induced damage, co-immunoprecipitation, yeast two-hybrid, siRNA knockdown with repair assays in human cells

    PMID:17353262 PMID:17507382

    Open questions at the time
    • Nature of the zinc finger-dependent recruitment mechanism was undefined
    • Precise function in NHEJ vs. single-strand break repair was unclear
    • Physiological consequence of ATM phosphorylation at Ser-116 was unknown
  2. 2008 High

    The zinc finger-dependent recruitment was resolved: APLF PBZ domains bind poly(ADP-ribose) directly, providing a PAR-dependent pathway to DNA damage sites parallel to the FHA–XRCC1 axis, and APLF was shown to interact with both Ku and XRCC4–DNA ligase IV, placing it within the NHEJ machinery.

    Evidence PAR-binding assays, in vitro CK2 phosphorylation, co-immunoprecipitation with domain mutants, NHEJ functional assay

    PMID:18077224 PMID:18474613

    Open questions at the time
    • Structural basis of PBZ–PAR recognition was unknown
    • How APLF promotes NHEJ mechanistically (scaffold vs. enzymatic) was unclear
  3. 2010 High

    NMR and crystallographic structures of the APLF PBZ domains revealed a novel zinc finger fold and identified specific aromatic residues (Y381/Y386, Y423/Y428) that engage adenine rings of ADP-ribose, providing the atomic-level mechanism for PAR recognition.

    Evidence NMR solution structures, crystal structures, site-directed mutagenesis with in vivo recruitment assays

    PMID:20098424 PMID:20439749

    Open questions at the time
    • Role of PAR chain length and branching in APLF binding affinity was not determined
    • Contribution of PBZ-mediated recruitment relative to FHA pathway in physiological repair was not quantified
  4. 2011 High

    Two simultaneous studies established that (1) PARP-3 generates PAR at DSBs to recruit APLF, which promotes XRCC4–Lig4 chromatin retention for NHEJ, and (2) APLF acts as a histone chaperone through its acidic domain, binding H3–H4 tetramers and contributing to DNA repair through chromatin remodeling.

    Evidence Aplf−/− mouse B cells with class switch recombination assay, epistasis with PARP3, histone binding pulldowns, in vitro chaperone assays, domain mutagenesis

    PMID:21211721 PMID:21211722

    Open questions at the time
    • Whether histone chaperone and NHEJ scaffold functions operate independently or are coordinated was unknown
    • The structural basis for histone octamer assembly by the acidic domain was not resolved
  5. 2012 High

    The Ku80 vWA domain was identified as the docking site for APLF, which then scaffolds XRCC4–Lig4 and XLF into a multi-protein complex capable of efficient DNA ligation, establishing APLF as a central NHEJ assembly factor rather than a catalytic enzyme.

    Evidence In vitro DNA ligation reconstitution, domain mutagenesis, siRNA and gene knockout in avian and human cells, cellular survival assays

    PMID:23178593

    Open questions at the time
    • Precise binding interface on Ku80 vWA domain was not structurally resolved
    • Stoichiometry of APLF within the complete NHEJ complex was unknown
  6. 2013 High

    ATM phosphorylation of APLF at Ser-116 was shown to depend on PARP3 and the PBZ domains, and to be functionally required for DSB repair kinetics, linking PARP3-dependent PAR signaling to ATM-dependent phosphorylation of APLF. Separately, a conserved Ku-binding motif was mapped and shown to be essential for NHEJ and nuclear retention.

    Evidence Phospho-specific antibodies, siRNA and chemical inhibition, phospho-mutant analysis, in vitro KBM peptide reconstitution, NHEJ reporter assays

    PMID:23449221 PMID:23689425

    Open questions at the time
    • Downstream effectors of Ser-116 phosphorylation were not identified
    • Relationship between KBM-mediated Ku binding and nuclear import was not fully dissected
  7. 2016 High

    SAXS analyses revealed that APLF is largely intrinsically disordered and stabilizes an extended six-protein NHEJ core complex (Ku70/80, DNA-PKcs, XRCC4–Lig4), providing a solution-state architectural model for how APLF organizes the ligation machinery around DNA ends.

    Evidence Small-angle X-ray scattering with in vitro reconstituted complex, mutagenesis

    PMID:27875301

    Open questions at the time
    • High-resolution structure of the full APLF-containing NHEJ complex was lacking
    • Dynamic rearrangements during end processing and ligation were not captured
  8. 2017 High

    Crystal structures of the APLF FHA domain bound to phosphorylated XRCC1 peptides provided atomic detail for how CK2-phosphorylated FHA-binding motifs recruit APLF to the single-strand break repair complex and support nuclear co-transport.

    Evidence X-ray crystallography, NMR, fluorescence polarization binding assays, mutagenesis

    PMID:29059378

    Open questions at the time
    • Whether APLF–XRCC1 and APLF–XRCC4 FHA interactions are mutually exclusive or simultaneous was not determined
  9. 2018 High

    Crystal structures of APLF and XLF KBMs bound to Ku–DNA complexes revealed that both bind distinct remote sites on the Ku80 α/β domain, and NMR-based mapping of the acidic domain showed how aromatic anchors engage α1–α2 patches on H2A–H2B to shield their DNA-binding surfaces, mechanistically explaining both scaffold and chaperone functions at atomic resolution.

    Evidence X-ray crystallography of Ku–KBM complexes, NMR of APLFAD–histone complexes, mutagenesis, radiosensitivity and chaperone assays

    PMID:29905837 PMID:30291363

    Open questions at the time
    • How histone chaperone activity is spatially and temporally coordinated with NHEJ ligation at the same break was not resolved
  10. 2022 High

    The crystal structure of the APLFAD–histone octamer complex demonstrated that APLF holds all eight histones in their nucleosomal conformation and deposits intact octamers onto DNA in a single step, distinguishing APLF from stepwise chaperones, while single-molecule magnetic tweezers showed that APLF's acidic region also stabilizes Ku-dependent DNA end synapsis.

    Evidence X-ray crystallography of APLFAD–octamer complex, nucleosome assembly reconstitution, magnetic tweezers with domain deletion mutants

    PMID:35895815 PMID:36640344

    Open questions at the time
    • Whether octamer deposition and DNA synapsis functions of the acidic domain are performed simultaneously or sequentially at a DSB is unknown
    • Contribution of lncRNA NIHCOLE to APLF-dependent synapsis in vivo was not established
  11. 2024 Medium

    APLF was found to participate in replication fork protection and interstrand crosslink repair through PARP1/PBZ-dependent recruitment that enables FANCD2 loading at stalled forks, expanding its roles beyond classical NHEJ.

    Evidence siRNA depletion, proximity ligation assay, DNA fiber assay for nascent strand degradation, ICL repair assay, PARP inhibition

    PMID:38520407

    Open questions at the time
    • Mechanism by which APLF enables FANCD2 loading is unknown (direct vs. indirect)
    • Not independently replicated
    • Whether histone chaperone activity contributes to fork protection was not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how APLF's scaffold, histone chaperone, and DNA synapsis functions are temporally coordinated at a single DSB; whether the reported kinase activity is physiologically relevant; and how APLF's roles in fork protection and ICL repair relate to its NHEJ functions.
  • No time-resolved in vivo data integrating APLF's multiple activities at a single break
  • Claimed kinase activity (PMID:38968704) is from a single lab with limited validation
  • Structural basis for APLF-mediated FANCD2 recruitment is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 3 GO:0044183 protein folding chaperone 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 2
Pathway
R-HSA-73894 DNA Repair 8 R-HSA-4839726 Chromatin organization 3
Partners
LIG4PARP1PARP3XLFXRCC1XRCC4XRCC5XRCC6
Complex memberships
NHEJ core complex (Ku70/Ku80–DNA-PKcs–XRCC4–Lig4–XLF)

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 APLF (C2orf13) accumulates at sites of chromosomal DNA damage via two mechanisms: (1) FHA domain-mediated interaction with XRCC1 (stimulated by CK2 phosphorylation) and (2) a C-terminal zinc finger motif-dependent, XRCC1-independent mechanism. APLF also interacts with XRCC4 and XRCC5 (Ku86) by yeast two-hybrid, and is phosphorylated in an ATM-dependent manner following DNA damage. In vivo co-immunoprecipitation, YFP-tagged localization at laser-induced DNA damage sites, yeast two-hybrid, siRNA knockdown with strand break repair assay, ATM-dependent phosphorylation mapping Molecular and cellular biology High 17353262
2007 APLF (Xip1/C2orf13) is rapidly recruited to DNA break sites via its C-terminal zinc finger motif; its accumulation is delayed and sustained when PARP-1 is inhibited. APLF stably interacts with XRCC1 through recognition of CK2-phosphorylated FHA-binding motifs in XRCC1, and XRCC1 is required to maintain steady-state APLF levels. APLF is phosphorylated at Ser-116 by ATM in response to ionizing radiation. GFP-tagged recruitment kinetics, PARP-1 inhibition, co-immunoprecipitation, siRNA knockdown, clonogenic survival assay The Journal of biological chemistry High 17507382
2008 The C-terminal tandem zinc finger (PBZ) domain of APLF binds tightly to poly(ADP-ribose) (PAR), enabling APLF accumulation at DNA strand breaks independently of its FHA domain. APLF negatively affects PAR levels in vitro, and overexpression of APLF or its zinc finger domain suppresses PAR appearance in cells in a zinc finger-dependent manner. PAR-binding assays, in vitro PAR modulation assay, overexpression in A549 cells with PAR immunodetection, domain deletion/mutation Molecular and cellular biology High 18474613
2008 APLF interacts with both Ku and XRCC4-DNA ligase IV in human cells. The APLF-XRCC4-DNA ligase IV interaction is FHA domain-dependent and phospho-dependent, mediated by CK2 phosphorylation of XRCC4 in vitro. APLF associates with Ku independently of its FHA and zinc finger domains and complexes with Ku at DNA ends. ATM phosphorylates APLF at Ser-116 after ionizing radiation. siRNA depletion of APLF impairs NHEJ. Co-immunoprecipitation, in vitro CK2 phosphorylation assay, domain mutant analysis, siRNA knockdown, NHEJ assay DNA repair High 18077224
2010 Solution NMR structures of the two PBZ domains of APLF were determined, revealing a novel zinc finger fold. NMR interaction studies with PAR fragments, combined with in vivo PAR-binding data, defined the structural basis for PBZ-PAR recognition. NMR solution structure determination, in vivo PAR-binding assays Nature structural & molecular biology High 20098424
2010 Structural and biochemical analyses identified Y381/Y386 and Y423/Y428 residues in the conserved C(M/P)Y and CYR motifs within each APLF PBZ domain as critical for interaction with the adenine ring of ADP-ribose; basic residues R387 and R429 coordinate additional interactions with the phosphate backbone. These residues are required for APLF recruitment to sites of DNA damage in vivo. Crystal structure/NMR, biochemical binding assays, site-directed mutagenesis, in vivo recruitment assays Proceedings of the National Academy of Sciences of the United States of America High 20439749
2011 PARP-3 is stimulated by DNA double-strand breaks in vitro and functions in the same pathway as APLF to accelerate NHEJ. PARP-3 promotes accumulation of APLF at DSBs, and APLF promotes retention of the XRCC4/DNA ligase IV complex in chromatin. Class switch recombination in Aplf-/- B cells is biased toward microhomology-mediated end-joining; overexpression of XRCC4/DNA ligase IV circumvents the requirement for PARP-3 and APLF. Genetic epistasis (Aplf-/- mouse cells), in vitro PARP-3 activation assay, chromatin fractionation, class switch recombination assay, overexpression rescue Molecular cell High 21211721
2011 APLF functions as a DNA-damage-specific histone chaperone. It preferentially binds the histone H3/H4 tetramer via its C-terminal acidic motif (homologous to NAP1L family motif). APLF exhibits histone chaperone activities in an acidic domain-dependent manner, and the NAP1L motif is critical for its DNA repair capacity in vivo. Histone binding assays (pulldown with H3/H4 tetramer), histone chaperone assays in vitro, domain deletion mutagenesis, in vivo DNA repair assay Molecular cell High 21211722
2012 The vWA domain of Ku80 recruits APLF into Ku-DNA complexes. APLF then acts as a scaffold promoting recruitment and/or retention of XRCC4-Lig4 and XLF, assembling multi-protein Ku complexes capable of efficient DNA ligation in vitro and in cells. Disruption of APLF interactions with Ku80 or XRCC4-Lig4 confers cellular hypersensitivity and reduced DSB repair. Co-immunoprecipitation, in vitro DNA ligation assay, domain mutagenesis, siRNA/gene knockout in avian and human cells, cellular survival assay The EMBO journal High 23178593
2013 ATM phosphorylation of APLF at Ser-116 is dependent on PARP3 levels and the APLF PBZ domains. Depletion or chemical inhibition of ATM or PARP3 reduces APLF accumulation at laser-induced DNA damage sites. Ser-116 phosphorylation is required for efficient DSB repair kinetics and cell survival after ionizing radiation, placing PARP3 and ATM in a common signaling pathway upstream of APLF phosphorylation. Phosphospecific antibodies, siRNA depletion, chemical inhibitors, laser-induced DNA damage recruitment assay, DSB repair kinetics assay, cell survival assay Nucleic acids research High 23449221
2013 An evolutionarily conserved Ku-binding motif (KBM) within APLF mediates the physical interaction between APLF and Ku heterodimer, with peptides derived from this region sufficient to reconstitute Ku binding in vitro. Disruption of this motif relocalizes APLF to the cytoplasm, reduces XRCC4 association, and impairs NHEJ and APLF retention at DNA damage sites; nuclear localization signal rescue restores these defects. In vitro peptide reconstitution of Ku interaction, mutagenesis, immunofluorescence localization, NHEJ reporter assay, laser damage recruitment assay The Journal of biological chemistry High 23689425
2016 APLF is largely an intrinsically disordered protein that binds Ku, Ku/DNA-PKcs (DNA-PK), and XRCC4-DNA ligase IV within an extended flexible NHEJ core complex. SAXS analyses reveal the solution architecture of a six-protein complex where APLF stabilizes assembly of Ku, DNA-PKcs, and X4L4, providing geometric access for ligation and phosphorylation. Small angle X-ray scattering (SAXS), mutational analyses, in vitro complex reconstitution The Journal of biological chemistry High 27875301
2017 Crystal structure of the APLF FHA domain bound to phosphorylated XRCC1 peptides revealed the structural basis of FHA-FBM interaction, including pH dependence due to atypical pK values of phosphoserine/phosphothreonine residues. Binding affinity is enhanced by flanking residues through non-specific electrostatic interactions, supporting XRCC1-mediated nuclear co-transport of APLF. X-ray crystallography, NMR, fluorescence polarization binding assay, mutagenesis Nucleic acids research High 29059378
2018 Crystal structures of the Ku-binding motifs (KBMs) of APLF (A-KBM) and XLF (X-KBM) bound to a Ku-DNA complex showed that both KBMs bind remote sites on the Ku80 α/β domain, with the X-KBM occupying a pocket formed by unprecedented outward rotation of Ku80. Mutation of A-KBM and X-KBM binding sites in Ku80 compromises end-joining efficiency, accuracy, and cellular radiosensitivity. X-ray crystallography, laser irradiation recruitment assay, mutagenesis, radiosensitivity assay Nature structural & molecular biology High 30291363
2018 The acidic domain of APLF (APLFAD) is intrinsically disordered and binds histone complexes (H3-H4)2 and H2A-H2B specifically and with high affinity. APLFAD prevents unspecific H2A-H2B-DNA complex formation (chaperone activity). NMR and mutagenesis showed that two aromatic side chains in APLFAD anchor to α1-α2 patches on H2A and H2B, covering most of their DNA-interaction surface. NMR structural studies, histone binding assays, chaperone activity assay, mutagenesis Nucleic acids research High 29905837
2016 Downregulation of APLF in mouse embryonic fibroblasts promotes reprogramming to iPSCs by augmenting E-cadherin (Cdh1) expression through expediting loss of repressive MacroH2A.1 from the Cdh1 promoter and enhancing incorporation of active H3me2K4 marks at pluripotency gene (Nanog, Klf4) promoters. shRNA knockdown, ChIP for histone modifications, iPSC reprogramming efficiency assay Journal of cell science Medium 27875275
2022 The crystal structure of the APLFAD-histone octamer complex shows that APLFAD tethers histones in their nucleosomal conformation. APLF acidic domain can assemble the histone octamer in a single step and deposit it on DNA to form nucleosomes. Mutations of key aromatic anchor residues in APLFAD affect chaperone activity in vitro and in cells. X-ray crystallography of APLFAD-histone octamer complex, nucleosome assembly assay, mutagenesis, cell-based assay Science advances High 35895815
2022 APLF stabilizes DNA end bridging (synapsis) and, together with Ku70-Ku80, establishes a minimal complex that supports DNA synapsis under piconewton forces for several minutes. The C-terminal acidic region of APLF is critical for DNA end bridging. lncRNA NIHCOLE further increases synapsis dwell time in the presence of Ku70-Ku80 and APLF. Magnetic tweezers assay, domain deletion (C-terminal acidic region mutants), in vitro reconstitution with purified proteins Cell reports High 36640344
2024 APLF is recruited to stalled replication forks via PARP1 activity (through its PBZ domain binding to PAR). APLF recruitment enables FANCD2 recruitment to stalled forks. APLF depletion impairs interstrand crosslink (ICL) repair, reduces FANCD2 at stalled forks, and causes nascent DNA degradation by MRE11, establishing a novel role for APLF in fork protection. siRNA depletion, proximity ligation assay/ChIP for fork association, ICL repair assay, nascent DNA degradation assay (DNA fiber), PARP inhibition Nucleic acids research Medium 38520407
2024 Nuclear localization of APLF in breast cancer cells is facilitated by PARP1, which transports APLF from cytosol to nucleus. PARP1 inhibition (olaparib) abrogates nuclear APLF expression and reduces EMT gene expression. Nuclear APLF in non-metastatic MCF7 cells (via NLS tagging) confers increased migration, invasion, and metastatic potential. Stable NLS-tagged APLF expression, PARP1 inhibition with olaparib, immunofluorescence localization, migration/invasion assays, in vivo metastasis assay Biochimica et biophysica acta. Molecular basis of disease Medium 39384105
2024 Mouse APLF possesses kinase activity (established by enzymatic analysis). APLF co-localizes with γ-tubulin at centrosomes in mouse embryonic stem cells and governs centrosome number and integrity via PLK4 phosphorylation. Mutagenesis of R37 in the FHA domain abolishes kinase activity and disrupts centrosome number regulation. Immunofluorescence co-localization, enzymatic kinase assay, docking studies, site-directed mutagenesis (R37A), domain deletion analysis European journal of cell biology Low 38968704

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 PARP-3 and APLF function together to accelerate nonhomologous end-joining. Molecular cell 265 21211721
2011 DNA repair factor APLF is a histone chaperone. Molecular cell 135 21211722
2007 APLF (C2orf13) is a novel human protein involved in the cellular response to chromosomal DNA strand breaks. Molecular and cellular biology 130 17353262
2012 APLF promotes the assembly and activity of non-homologous end joining protein complexes. The EMBO journal 115 23178593
2018 XLF and APLF bind Ku80 at two remote sites to ensure DNA repair by non-homologous end joining. Nature structural & molecular biology 90 30291363
2010 Solution structures of the two PBZ domains from human APLF and their interaction with poly(ADP-ribose). Nature structural & molecular biology 87 20098424
2016 CEP5 and XIP1/CEPR1 regulate lateral root initiation in Arabidopsis. Journal of experimental botany 85 27296247
2008 APLF (C2orf13) is a novel component of poly(ADP-ribose) signaling in mammalian cells. Molecular and cellular biology 82 18474613
2010 Structure and identification of ADP-ribose recognition motifs of APLF and role in the DNA damage response. Proceedings of the National Academy of Sciences of the United States of America 81 20439749
2008 APLF (C2orf13) facilitates nonhomologous end-joining and undergoes ATM-dependent hyperphosphorylation following ionizing radiation. DNA repair 76 18077224
2007 Human Xip1 (C2orf13) is a novel regulator of cellular responses to DNA strand breaks. The Journal of biological chemistry 66 17507382
2016 An Intrinsically Disordered APLF Links Ku, DNA-PKcs, and XRCC4-DNA Ligase IV in an Extended Flexible Non-homologous End Joining Complex. The Journal of biological chemistry 60 27875301
2013 The PARP3- and ATM-dependent phosphorylation of APLF facilitates DNA double-strand break repair. Nucleic acids research 54 23449221
2018 DNA repair factor APLF acts as a H2A-H2B histone chaperone through binding its DNA interaction surface. Nucleic acids research 41 29905837
2013 Identification and functional characterization of a Ku-binding motif in aprataxin polynucleotide kinase/phosphatase-like factor (APLF). The Journal of biological chemistry 35 23689425
2019 Rewiring E2F1 with classical NHEJ via APLF suppression promotes bladder cancer invasiveness. Journal of experimental & clinical cancer research : CR 22 31287003
2018 Lateral root growth in Arabidopsis is controlled by short and long distance signaling through the LRR RLKs XIP1/CEPR1 and CEPR2. Plant signaling & behavior 22 29993313
2022 Chaperoning of the histone octamer by the acidic domain of DNA repair factor APLF. Science advances 17 35895815
2018 Enhanced expression of histone chaperone APLF associate with breast cancer. Molecular cancer 15 29580241
2022 APLF and long non-coding RNA NIHCOLE promote stable DNA synapsis in non-homologous end joining. Cell reports 13 36640344
2016 Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts. Journal of cell science 11 27875275
2024 APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance. Nucleic acids research 10 38520407
2020 End Processing Factor APLF Promotes NHEJ Efficiency and Contributes to TMZ- and Ionizing Radiation-Resistance in Glioblastoma Cells. OncoTargets and therapy 9 33116637
2017 Characterization of the APLF FHA-XRCC1 phosphopeptide interaction and its structural and functional implications. Nucleic acids research 8 29059378
2021 Histone chaperone APLF level dictates the implantation of mouse embryos. Journal of cell science 6 33277378
2025 Aplf/Dna2 variants drive chromosomal fission and accelerate speciation in zokors. Science advances 3 40911670
2024 Kinase activity of histone chaperone APLF maintains steady state of centrosomes in mouse embryonic stem cells. European journal of cell biology 1 38968704
2024 Nuclear localization of APLF facilitates breast cancer metastasis. Biochimica et biophysica acta. Molecular basis of disease 0 39384105