PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility.

C. Godon, F. P. Cordelieres, D. Biard, N. Giocanti, F. Megnin-Chanet, J. Hall, V. Favaudon
Nucleic Acids Research. 2008-06-27; 36(13): 4454-4464
DOI: 10.1093/nar/gkn403

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1. Nucleic Acids Res. 2008 Aug;36(13):4454-64. doi: 10.1093/nar/gkn403. Epub 2008
Jul 4.

PARP inhibition versus PARP-1 silencing: different outcomes in terms of
single-strand break repair and radiation susceptibility.

Godon C(1), Cordelières FP, Biard D, Giocanti N, Mégnin-Chanet F, Hall J,
Favaudon V.

Author information:
(1)Institut Curie, Centre de Recherche Inserm, U612, Institut Curie, Bât.
110-112, Centre Universitaire, F-91405 Orsay, France.

The consequences of PARP-1 disruption or inhibition on DNA single-strand break
repair (SSBR) and radio-induced lethality were determined in synchronized,
isogenic HeLa cells stably silenced or not for poly(ADP-ribose) polymerase-1
(PARP-1) (PARP-1(KD)) or XRCC1 (XRCC1(KD)). PARP-1 inhibition prevented XRCC1-YFP
recruitment at sites of 405 nm laser micro irradiation, slowed SSBR 10-fold and
triggered the accumulation of large persistent foci of GFP-PARP-1 and GFP-PCNA at
photo damaged sites. These aggregates are presumed to hinder the recruitment of
other effectors of the base excision repair (BER) pathway. PARP-1 silencing also
prevented XRCC1-YFP recruitment but did not lengthen the lifetime of GFP-PCNA
foci. Moreover, PARP-1(KD) and XRCC1(KD) cells in S phase completed SSBR as
rapidly as controls, while SSBR was delayed in G1. Taken together, the data
demonstrate that a PARP-1- and XRCC1-independent SSBR pathway operates when the
short patch repair branch of the BER is deficient. Long patch repair is the
likely mechanism, as GFP-PCNA recruitment at photo-damaged sites was normal in
PARP-1(KD) cells. PARP-1 silencing elicited hyper-radiosensitivity, while
radiosensitization by a PARP inhibitor reportedly occurs only in those cells
treated in S phase. PARP-1 inhibition and deletion thus have different outcomes
in terms of SSBR and radiosensitivity.

DOI: 10.1093/nar/gkn403
PMCID: PMC2490739
PMID: 18603595 [Indexed for MEDLINE]

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