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Function of the ARH Family of ADP-ribose-acceptor Hydrolases

Wednesday, November 06, 2013 — Poster Session I

4:00 p.m. – 6:00 p.m.

FAES Academic Center (Upper-Level Terrace)




  • J Kato
  • M Mashimo
  • X Bu
  • H Endo
  • J Moss


ADP-ribosylation, a reaction where the ADP-ribose of NAD is transferred to acceptors is used by bacterial toxins to disrupt cell function. In mammalian cells, ADP-ribosylation is regulated by ADP-ribosyltransferases that transfer ADP-ribose and ADP-ribose-acceptor hydrolases (e.g., ARHs) that cleave the ADP-ribose-acceptor bond. ARH1 preferentially hydrolyzes ADP-ribose-arginine. ARH3 hydrolyzes O-acetyl-ADP-ribose and poly(ADP-ribose) (PAR) but not ADP-ribose-arginine. Female ARH1-deficient and heterozygous mice developed tumors with increased frequency. Tumor growth following injection of ARH1-deficient and heterozygous mouse embryonic fibroblasts (MEFs) subcutaneously into nude mice was more rapid in female mice. The functioning allele was mutated in tumors from heterozygous mice and MEFs, suggesting that ARH1 is a tumor suppressor gene. Biological activities of ARH3 were examined using ARH3-deficient mice and MEFs. ARH3-deficient MEFs showed decreased viability in the presence of hydrogen peroxide, with increased PAR in the nucleus and cytoplasm. Cytoplasmic PAR is responsible for apoptosis-inducing factor (AIF) release from mitochondria. AIF subsequently translocates to the nucleus where it is responsible for cell death. The ARH3-deficient mouse under stress conditions is similarly more sensitive to injury. These data suggest that ARH1 and ARH3 have different roles in the regulation of biological processes in health and disease. Funding: Intramural Research Program, NIH, NHLBI.

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