title: APLF (C2orf13) is a novel component of poly(ADP-ribose) signaling in mammalian cells.
abstract: 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(ADP-ribosyl)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.
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Science Park Road, Falmer, Brighton BN1 9RQ, United Kingdom.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Rulten
authors.forename: Felipe
authors.initials: F
authors.lastname: Cortes-Ledesma
authors.forename: Liandi
authors.initials: L
authors.lastname: Guo
authors.forename: Natasha J
authors.initials: NJ
authors.lastname: Iles
authors.forename: Keith W
authors.initials: KW
authors.lastname: Caldecott
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D006801:Humans; D010750:Phosphoproteins / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D015398:Signal Transduction; D016335:Zinc Fingers
chemical_list: D010750:Phosphoproteins; D000075223:Poly-ADP-Ribose Binding Proteins; D000246:Adenosine Diphosphate Ribose; C520557:APLF protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase