Abstract
The DNA damage dependence of poly(ADP-ribose) polymerase-2 (PARP-2) activity is suggestive of its implication in genome surveillance and protection. Here we show that the PARP-2 gene, mainly expressed in actively dividing tissues follows, but to a smaller extent, that of PARP-1 during mouse development. We found that PARP-2 and PARP-1 homo- and heterodimerize; the interacting interfaces, sites of reciprocal modification, have been mapped. PARP-2 was also found to interact with three other proteins involved in the base excision repair pathway: x-ray cross complementing factor 1 (XRCC1), DNA polymerase beta, and DNA ligase III, already known as partners of PARP-1. XRCC1 negatively regulates PARP-2 activity, as it does for PARP-1, while being a polymer acceptor for both PARP-1 and PARP-2. To gain insight into the physiological role of PARP-2 in response to genotoxic stress, we developed by gene disruption mice deficient in PARP-2. Following treatment by the alkylating agent N-nitroso-N-methylurea (MNU), PARP-2-deficient cells displayed an important delay in DNA strand breaks resealing, similar to that observed in PARP-1 deficient cells, thus confirming that PARP-2 is also an active player in base excision repair despite its low capacity to synthesize ADP-ribose polymers.
Highlights
In response to DNA interruptions, PARP-1,1 the founding member of the poly(ADP-ribose) polymerase superfamily, catalyzes the successive covalent addition of ADP-ribose units from NAD to a limited number of nuclear acceptors to form a branched anionic polymer
Following treatment by the alkylating agent N-nitroso-N-methylurea (MNU), poly(ADP-ribose) polymerase-2 (PARP-2)-deficient cells displayed an important delay in DNA strand breaks resealing, similar to that observed in PARP-1 deficient cells, confirming that PARP-2 is an active player in base excision repair despite its low capacity to synthesize ADP-ribose polymers
PARP-2 Belongs to a BER Complex Containing x-ray cross complementing factor 1 (XRCC1), PARP-1, DNA pol, and DNA Ligase III—Given that PARP-1 is involved in base excision repair through its association with the scaffold protein XRCC1 [2,3,4], we examined whether
Summary
In response to DNA interruptions, PARP-1,1 the founding member of the poly(ADP-ribose) polymerase superfamily, catalyzes the successive covalent addition of ADP-ribose units from NAD to a limited number of nuclear acceptors to form a branched anionic polymer. Identification of the Domains Involved in the Association of PARP-2 with PARP-1—To map the interaction domain within PARP-1, GST fusion proteins were generated expressing truncated versions of hPARP-1 (Fig. 4A): amino acids 1–371 (A–C, the DNA binding domain), amino acids 174 –366 (B and C), amino acids 384 –524 (D, encompassing the BRCT domain), amino acids 572–1014 (F, encompassing the catalytic domain), and amino acids 525– 655 (region E).
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