parp 1 e 2

7/29/2019 parp 1 e 2

1/6

DNA Repair 3 (2004) 11031108

Review

PARP-1, PARP-2 and ATM in the DNA damage response:functional synergy in mouse development

Aline Huber, Peter Bai, Josiane Mnissier de Murcia, Gilbert de Murcia

Unit 9003 du CNRS, Ecole Suprieure de Biotechnologie de Strasbourg, Boulevard Sbastien Brant, BP 10413, 67412 Illkirch Cedex, France

Available online 23 June 2004

Abstract

Poly(ADP-ribosyl)ation is an immediate DNA damage-dependent posttranslational modification of histones and nuclear proteins thatcontributes to the survival of injured proliferating cells. Poly(ADP-ribose) polymerases (PARPs) now constitute a superfamily of 18 proteins,

encoded by different genes and displaying a common conserved catalytic domain. PARP-1 (113 kDa), the founding member, and PARP-2

(62kDa)are both involved in DNA-break sensing andsignaling when singlestrand break repair(SSBR)or base excisionrepair (BER) pathways

are engaged. The generation by homologous recombination of deficient mouse models have confirmed the caretaker function of PARP-1 and

PARP-2 in mammalian cells under genotoxic stress. This review summarizes our present knowledge on their physiological role in the cellular

response to DNA damageand on thegenetic interactionsbetween PARP-1, PARP-2,Atm that play an essentialrole during early embryogenesis.

2004 Elsevier B.V. All rights reserved.

Keywords: PARP-1; PARP-2; ATM

1. PARP-1 and PARP-2, two DNA damage-dependent

enzymes of a large superfamily

The presence of DNA strand breaks in the cells of

higher eukaryotes activate signal transduction pathways

that trigger cell cycle arrest and repair mechanisms lead-

ing ultimately to cell survival or programmed cell death.

Central to pathways that maintain genomic integrity is the

immediate modification of histones and nuclear proteins by

ADP-ribose polymers catalyzed by poly(ADP-ribose) poly-

merases (PARPs) [1]. A large repertoire of 18 sequences

encoding novel PARPs now extend considerably the field

of poly(ADP-ribosyl)ation reactions to various aspects of

the cell biology including cell proliferation, cell death and

energy metabolism. The members of the PARP superfamilyare characterized by a conserved core responsible for the

catalytic activity to which a number of specific targeting

and regulatory modules have been added. This modular ar-

chitecture of PARPs lead to a plethora of possible functions,

perhaps broader than genome surveillance [2].

PARP-1 and PARP-2, are so far the sole members whose

catalytic activity stimulated in vitro and in vivo by DNA

Corresponding author. Tel.: +33 388 90 24 47 07;

fax: +33 388 90 24 46 86.

E-mail address: [email protected] (G.de Murcia).

strand-breaks [3,4] catalyze the transfer of the ADP-ribose

moiety from the respiratory co-enzyme NAD+

to a limitednumber of acceptor proteins involved in chromatin architec-

ture and in DNA metabolism (Fig. 1A).

PARP-1 (113 kDa) is a multifunctional enzyme, highly

conserved from human to A. thaliana, but absent in yeast.

Its domain structure comprises (i) a N-terminal DNA break

recognition module containing a duplicated zinc finger, ho-

mologous to that of DNA ligase III (ii) a central BRCT motif,

present in a large number of proteins involved in the mainte-

nance of genomic integrity and cell cycle checkpoints, acting

as the major proteinprotein interacting interface and (iii)

a carboxy-terminal region bearing all the different catalytic

activities associated with the full-length enzyme: NAD+ hy-

drolysis and initiation, elongation, branching and termina-tion of ADP-ribose polymers (Fig. 1B). The basal activity of

PARP-1 is stimulated 500 times by the presence of breaks in

the DNA. The catalytic domain is by far the most evolution-

arily conserved region. It contains a block of 50 amino acids

(aa 859908), the PARP signature, virtually unchanged

from human to plants [1]. It is conserved to various degree

among the 18 human PARP orthologs [2].

PARP-2 (62 kDa) was discovered as a result of the pres-

ence of residual DNA-dependent PARP activity in embry-

onic fibroblasts derived from PARP-1-deficient mice [3].

PARP-2 is responsible for only 1015% of the total PARP

1568-7864/$ see front matter 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.dnarep.2004.06.002

7/29/2019 parp 1 e 2

2/6

1104 A. Huber et al./ DNA Repair 3 (2004) 11031108

Fig. 1. (A) Metabolism of poly(ADP-ribose) during DNA damage and repair induced by various genotoxins. (B) The domain structure of the two DNA

damage-dependent human poly(ADP-ribose) polymerases-1 and -2 (PARP-1, PARP-2). PARG, poly(ADP-ribose) glycohydrolase; NLS, nuclear localizationsignal. BRCT; BRCA1 C-terminus motif. Nam; nicotinamide.

activity fully stimulated by DNA strand-breaks in a cellular

extract. Its catalytic domain has the strongest resemblance

among all the other family members to that of PARP-1 with

69% similarity. Structural studies of the murine PARP-2

demonstrated that its catalytic domain is very similar to that

of PARP-1 except in the vicinity of the acceptor site that is

most probably specific for protein substrates [5]. PARP-2 is

a nuclear protein that binds to and is activated in vitro by

DNase-I treated DNA. However, its DNA binding domain

differs from that of PARP-1 and targets DNA gaps but not

nicks (Am et al., in preparation). The N-terminal domain

of PARP-2, 75 aa in size, is responsible both for the local-

ization of PARP-2 to the nucleus (Fig. 1B) and the recog-

nition of DNA interruptions. It displays homology with the

SAP domain found in various nuclear proteins like APE-1

and Ku70, involved in chromosomal organization and in

DNA repair. Interestingly, this domain is also found in plant

PARP-2, whose transcription is dramatically upregulated in

response to a sublethal dose of ionizing radiation (IR) [6].

PARP-2 acts as a chromatin modifier too but poly(ADP-

ribosyl)ates histone H2B while PARP-1 targets histone

H1. PARP-2 interacts with PARP-1, they share common

partners involved in the single strand break repair (SSBR)

and base excision repair (BER) pathways: XRCC1, DNA

polymerase-, and DNA ligase III [4] suggesting that they

are both engaged in the same DNA repair complex. PARP-1

and PARP-2 interact also with proteins involved in the

kinetochore structure and in the mitotic spindle checkpoint.

However, specific partners of PARP-2 are begining to be

discovered such as the telomeric protein TRF2 suggesting

a link with the control of telomere integrity [7].

2. Poly(ADP-ribosyl)ation, the first line of defense in

response to DNA breaks: for better or for worse

Several characteristics of PARP-1 behavior upon DNA

damage classify this fascinating enzyme as a component of

the early response to DNA strand breaks. Recent studies

from Okano et al. [8] and El-Khamisy et al. [9] as well as

work from our laboratory [10] reveals that the immediate

synthesis of PAR at a DNA strand break constitutes an initi-

ating event in a damaged cell. This, triggers the subsequent

co-ordination of DNA strand-breaks detection by PARP-1

7/29/2019 parp 1 e 2

3/6

A. Huber et al. / DNA Repair 3 (2004) 11031108 1105

Fig. 2. Scheme depicting the involvment of PARPs in the repair of

single strand breaks process. (i) Following SSB dection by PARP-1,

poly(ADP-ribose) synthesis at the DNA damage site triggers the immediate

recruitment of XRCC1 and the assembly of the SSBR repair complex

[37]. (ii) Polynucleotide kinase (PNK), stimulated by XRCC1, converts

the DNA ends to 5-phosphate and 3-hydroxyl moieties that (iii) enables

DNA Pol , stimulated by PARP-1, to fill the gap. The size of the repair

patch is controlled by the nuclease FEN1 and PARP-2. (iv) The ligationstep is finally catalyzed by DNA Lig III whose stability is controlled by

XRCC1. Closing of the break then abrogates PARPs activities.

and signaling to the SSBR pathway, the whole process being

performed in less than 15 s.

PARP-1 is particularly well suited to fulfill several key

functions following the occurrence of an interruption of

the sugar phosphate backbone: (i) efficient sensing of the

DNA break [11,12]; (ii) translation and amplification of

the damage signal in a posttranslational modification of

PARP-1 itself (automodification) and of histones H1 and

H2B (heteromodification) that triggers chromatin structure

relaxation [13] and increases the access to the break; (iii)

PAR-dependent recruitment of XRCC1 to the damaged site

[8] mediated by its BRCT1 motif that displays high affinity

to PAR and PARP-1 [14,15]. Although not essential in vitro,

XRCC1 as a scaffold protein with no known enzymatic func-

tion plays a critical role in the co-ordinated handling of the

damaged DNA, from one repair enzyme to the next, in the

BER pathway [16] (see Fig. 2). It is nevertheless essential

during mouse development [17]. The absence of PARP-1 or

the inhibition of its enzymatic activity totally prevents the

dynamic recruitment of XRCC1 to the break, thus explain-

ing the important delay in strand-break rejoining that causes

a severe DNA repair defect in PARP-1/ damaged cells

or in damaged cells treated with 3-AB. However, the repair

defect observed in PARP-2/ damaged cells [4] cannot be

attributed to a lack of XRCC1 recruitment, since this step

still occurred following DNA breakage [10]. Rather, PARP-2

activity seems to be associated to a subsequent step in the

SSBR pathway (Fig. 2).PARP-1 activity induced by high levels of DNA breaks

renders PARP-1 a risky cellular factor when the genome is

being degradated during cell death. Therefore, to limit futile

DNA repair during apoptosis and to preserve the NAD+ and

ATP pools, PARP-1 is inactivated by a caspase-dependent

cleavage [18]. A quite different scenario takes place in

acute pathophysiological conditions such as necrosis or

caspase-independent cell death (chromatinolysis) where

PARP-1 is instrumentalized by the Apoptosis-Inducing fac-

tor (AIF) a flavoprotein normally confined to the mitochon-

drial intermembrane space. In response to DNA injury, AIF

in concert with the EndoG nuclease translocates rapidly to

the nucleus and degradates the chromatin into 50 kb frag-

ments [19]. This large scale DNA fragmentation overacti-

vates PARP-1 and kills the cells in a caspase-independent

manner, thus leading to inflammatory injury in the corre-

sponding tissue [20,21]. Dawson and colleagues provided

evidence that PARP-1 initiates a nuclear signal that propa-

gates to mitochondria and triggers the release of AIF that

leads to cell death. Accordingly, PARP-1-deficient cells

or pharmacologically inhibited wild-type cells are fully

protected against excessive damage.

Clearly, the activation of PARP-1 has two opposed mean-

ings depending upon the cell type and the extend of the DNA

damage: (i) Survival: in replicating cells, limited damage toDNA induces PARP activity and stimulates the activation of

DNA repair pathways through the recruitment of DNA repair

factors (i.e. XRCC1). The decision for the cell to engage the

apoptotic pathway after genotoxic stress takes place down-

stream of p53 activation, but the molecular determinants that

switch between DNA repair and cell-cycle arrest or apopto-

sis are not yet fully understood. When apoptosis is induced,

PARP-1 and -2 as survival factors are cleaved by caspases

and are thus inactivated. (ii) Cell death: In post-mitotic cells,

reactive oxygen species (ROS) damage DNA activate PARP

and trigger AIF translocation to the nucleus. The resulting

DNA fragmentation overactivates PARP and leads to nu-clear condensation. Understanding the switch between these

two facets of PARP biology might ultimately improve phar-

macological strategies to enhance both antitumor efficacy

as well as the treatment of a number of inflammatory and

neurodegenerative disorders.

3. PARP-1- and PARP-2-deficient mice are highly

sensitive to DNA damage

To gain further insight into the functional importance of

DNA-dependent poly(ADP-ribosyl)ation reactions at the

7/29/2019 parp 1 e 2

4/6


animal level, we and others have generated PARP-1/

[2224] and PARP-2/ deficient mice [25]. Both mu-

tant mice are similarly radiosensitive and display severe

genomic instability after -irradiation. Mouse embryonic

fibroblasts (MEFs) lacking either PARP-1 [24,2628] or

PARP-2 [4] display a similar severe defect in alkylation in-

duced DNA strand-break resealing confirming that PARP-1and PARP-2 are involved in the maintenance of genomic in-

tegrity. Interestingly, the sensitization of PARP-2/ MEFs

is accompanied by a G2/M accumulation, the acquisition of

8N DNA content, the presence of anaphase bridges, and the

occurrence of preferential breaks in centromeric and sub-

centromeric regions reflecting kinetochore defects. Thus,

although PARP-2-specific activity is reduced compared

to that of PARP-1, the phenotype of the PARP-2/ and

PARP-1/ mice are equally severe, because they both par-

ticipate not in the catalytic steps of the process, but instead

they dramatically affect the efficiency and/or the accuracy

of the repair.

The double null mutant PARP-1/; PARP-2/ embryos

are not viable and die around E7.5 at the onset of gastrula-

tion, demonstrating that the expression of both PARP-1 and

PARP-2 and/or DNA-dependent poly(ADP-ribosyl)ation

is essential during early embryogenesis. Interestingly,

a specific female embryonic lethality is observed in

PARP-1+/PARP-2/ mutant at mid-gestation (E9.5).

Metaphase analyses of E8.5 embryonic fibroblasts highlight

a specific instability of the X-chromosome in those females

but not in males. [25]. These results support the notion

that, even if a critical level of the DNA repair capacity is

reached in PARP-1+/ PARP-2/ mutant, avoiding an

early lethality, the poor DNA repair efficiency may lead to asevere genomic instability, detrimental first to the females.

4. PARP-1, -2, Atm: genetic interactions in mouse

development

The multifunctional protein kinase Atm is an orchestrat-

ing factor in the cascade of events leading to activation of

the cellular response to DNA double strand breaks, which

includes repair and cell-cycle checkpoint pathways [29] (see

also Kurz and lees-Miller, in press). ATM is missing or in-

activated in patients with the genomic instability syndroma

ataxia-telangiectasia (A-T) (Chun and Gatti, in press). Cell

lines established from Atm-deficient mice, like those from

A-T patients exhibit genomic instability and defective re-

sponse to double strand breaks (DSBs), e.g., defective acti-

vation of the cell cycle checkpoints after ionizing radiation

[30] likely attributed to the defect in sensing, repairing and

signaling DSBs. Beside a clear defect in DSB response, A-T

cells may chronically suffer from increased oxidative stress

[31].

The relationship between ATM and PARP-1 on one hand

and ATM and PARP-2 on the other hand were so far unex-

plored in the mice. Two mouse models deficient for ATM

Fig. 3. External views and histological sections of E8.0 normal (a, c)

(N, normal and PARP-1/; Atm+/), (b, d) (PARP-1; Atm) double null

concepti (/; /), (e, f) (PARP-2; Atm) double null concepti (/;

/). Abbreviations: A, amnion; AL, allantois; EC, ectoplacental cavity;

EX, extraembryonic material; EM, embryo; F, foregut pocket; H, head

folds; P, placenta; S, somites; YC, yolk sac cavity. (Taken from ref. [38]

with permission.)

and PARP-1 (Atm/; PARP-1/) or PARP-2 (Atm/;

PARP-2/) were generated to investigate the impact of

these putative interactions on genomic stability and em-

bryonic development. No homozygous PARP-1, Atm and

PARP-2, Atm-disrupted pups were observed (Fig. 3 and

Table 1) implying that a potent synergistic interaction exists

between Atm and PARP-1 as well as Atm and PARP-2 that

impacts on the embryonic development. The double-null

mutants embryos die early in development, subsequent to

the gastrulation stage. During this restrictive developmental

window, undifferentiated stem cells that form the epiblast

sustain high cell division rate.

In proliferative state, intense metabolism during em-

bryonic growth is accompanied by an oxidative burst that

7/29/2019 parp 1 e 2

5/6

A. Huber et al. / DNA Repair 3 (2004) 11031108 1107

Table 1

Genotype analysis of (PARP; Atm) embryos from heterozygous matings

Intercross Age of progeny n No. of embryo (% of total) with Atm genotype

+/+ +/ /

PARP-1/; Atm+/ Newborn 123 30 (24) 93 (76) 0

E8.0E11.5 60 14 (24) 29 (48) 17 (28)a

PARP-2/; Atm+/ Newborn 163 59 (36) 104 (64) 0E8.5 38 10 (26) 19 (50) 9 (24)a

a Growth retarded embryos.

may cause oxidative damage to genomic DNA. This fea-

ture would be exacerbated in the double mutant embryos

by the perturbation of the cellular balance of reactive

oxygen species which leads to constant oxidative stress

in Atm-deficient cells [31]. Alternatively, the lower rate

of repair that we and others have previously shown in

PARP-1/ [26,27] and in PARP-2/ [4] cells combined

to Atm deficiency may have seriously weakened the cells

defense against endogenous DNA damage, increasing thelikelihood of lethal chromosomal breaks and replication

failure at a stage of development accompanied by rapid cell

division.

5. Concluding remarks

The phenotype displayed by each combinations of double

mutants are more severe than either of the single knockout

(Fig. 4) suggesting that Atm, PARP-1 and PARP-2 partici-

pate in overlapping DNA damage signaling pathways or reg-

ulate distinct forms of DNA repair that partially compensatefor each other. Interestingly, breeding experiments aimed at

generating deficient mice in both Ku80 and PARP-1 [32] and

Ku80 and Atm [33] also lead to early embryonic lethality at

the gastrulation stage. Thus, the loss of certain components

of the SSBR/BER and DSB repair pathways lead to massive

apoptosis of the embryo at the onset of gastrulation perhaps

as a result of unrepaired DNA damage or due to a defect in

DNA-damage signaling.

Interestingly, both PARPs, Atm and DNA PKcs are DNA

damage-dependent chromatin modifiers. In response to

DNA breaks, PARP-1 and PARP-2 poly(ADP-ribosyl)ate

histone H1 and H2B, causing the immediate relaxation

of the 30nm chromatin fiber, a necessary step to in-crease the access to the break [13,34]. Upon -irradiation,

the activation of the Atm kinase by autophosphorylation

Fig. 4. Early embryonic lethality and genetic interactions between PARP-1,

PARP-2, Atm and Ku80 (see text for references).

induced-monomerization has been shown recently to be

sensitive to conformational changes of chromatin [35] lead-

ing to histone H2AX phosphorylation of its C-terminal

tail on Ser-139. H2AX phosphorylation is now believed to

participate in chromatin reconfiguration and foci formation

that serve to increase the local concentration of DSB repair

factors and/or limit the diffusion of the broken DNA ends

until the break is repaired [36] (Fig. 5). Given that changes

in chromatin structure emanating from DNA breaks areprobably the most initiating events in the cellular response

to DNA damage, it is tempting to speculate that histone

modifications play an essential role, not only in DNA pack-

aging, but also monitoring the integrity of the mammalian

genome. The disruption of both PARPs and Atm routes

to chromatin may also explain the impossibility for the

resulting embryo to develope normally.

Fig. 5. Schematic representation of the DNA strand-breaks signaling

and processing pathway. The pathway is triggered by IR resulting in

single- and double-strand breaks that immediately initiate two posttrans-

lational modifications of histones and nuclear proteins catalyzed by DNA

damage-dependent PARPs and Atm. Poly(ADP-ribosyl)ation of histones

H1 and H2B increase chromatin accessibility at the actual site of DNA

damage thus promoting DNA repair. Phosphorylation of histone H2AX

by Atm occurs at or near the double-strand break and is required for the

phosphorylation of 53BP1 that participates to nuclear foci organization

and the subsequent recruitment of several Atm downstream targets.

7/29/2019 parp 1 e 2

6/6


Acknowledgements

We thank A. Wynshaw-Boris for the Atm-deficient mice.

P.B. was supported by a FEBS long-term fellowship. This

work was supported by funds from Centre National de la

Recherche Scientifique, Association pour la Recherche Con-

tre le Cancer, Electricit de France, Ligue Nationale Contrele Cancer and Commissariat lEnergie Atomique.

References

[1] G. de Murcia, S. Shall, From DNA damage and stress signalling

to cell death: poly(ADP-ribosylation) reactions, Oxford University

Press, Oxford, 2000, p. 238.

[2] J.-C. Am, C. Spenlehauer, G. de Murcia, The PARP superfamily,

Bioessays, 2004, in press.

[3] J.-C. Am, et al., PARP-2, a novel mammalian DNA damage-

dependent poly(ADP-ribose) polymerase, J. Biol. Chem. 274 (25)

(1999) 1786017868.

[4] V. Schreiber, et al., Poly(ADP-ribose) polymerase-2 (PARP-2) is re-quired for efficient base excision DNA repair in association with

PARP-1 and XRCC1, J. Biol. Chem. 277 (25) (2002) 23028

23036.

[5] A.W. Oliver, et al., Crystal structure of the catalytic fragment of

murine poly(ADP-ribose) polymerase-2, Nucleic Acids Res. 32 (2)

(2004) 456464.

[6] G. Doucet-Chabeaud, et al., Ionising radiation induces the expression

of PARP-1 and PARP-2 genes in Arabidopsis, Mol. Genet. Genomics

265 (6) (2001) 954963.

[7] F. Dantzer, et al., Functional interaction between poly(ADP-ribose)

polymerase 2 (PARP-2) and TRF2: PARP activity negatively regulates

TRF2, Mol. Cell Biol. 24 (4) (2004) 15951607.

[8] S. Okano, et al., Spatial and temporal cellular responses to

single-strand breaks in human cells, Mol. Cell Biol. 23 (11) (2003)

39743981.[9] S.F. El-Khamisy, et al., A requirement for PARP-1 for the assembly

or stability of XRCC1 nuclear foci at sites of oxidative DNA damage,

Nucleic Acids Res. 31 (19) (2003) 55265533.

[10] C. Spenlehauer et al., DNA damage signalling, in: W. Siede (Ed.),

2004.

[11] J. Menissier-de Murcia, et al., Zinc-binding domain of poly

(ADP-ribose)polymerase participates in the recognition of single

strand breaks on DNA, J. Mol. Biol. 210 (1) (1989) 229233.

[12] G. Gradwohl, et al., The second zinc-finger domain of poly(ADP-

ribose) polymerase determines specificity for single-stranded breaks

in DNA, Proc. Natl. Acad. Sci. U.S.A. 87 (8) (1990) 29902994.

[13] G.G. Poirier, et al., Poly(ADP-ribosyl)ation of polynucleosomes

causes relaxation of chromatin structure, Proc. Natl. Acad. Sci.

U.S.A. 79 (11) (1982) 34233427.

[14] J.M. Pleschke, et al., Poly(ADP-ribose) binds to specific domains inDNA damage checkpoint proteins, J. Biol. Chem. 275 (52) (2000)

4097440980.

[15] M. Masson, et al., XRCC1 is specifically associated with

poly(ADP-ribose) polymerase and negatively regulates its activity

following DNA damage, Mol. Cell Biol. 18 (6) (1998) 35633571.

[16] J.A. Tainer, Structural implications of BER enzymes: dragons

dancingthe structural biology of DNA base excision repair, Prog.

Nucleic Acid Res. Mol. Biol. 68 (2001) 299304.

[17] R.S. Tebbs, et al., Requirement for the Xrcc1 DNA base excision

repair gene during early mouse development, Dev. Biol. 208 (2)

(1999) 513529.

[18] S.H. Kaufmann, et al., Specific proteolytic cleavage of

poly(ADP-ribose) polymerase: an early marker of chemotherapy-

induced apoptosis, Cancer Res. 53 (17) (1993) 39763985.

[19] S.A. Susin, et al., Mitochondrial release of caspase-2 and -9 during

the apoptotic process, J. Exp. Med. 189 (2) (1999) 381394.

[20] S.W. Yu, et al., Mediation of poly(ADP-ribose) polymerase-1-

dependent cell death by apoptosis-inducing factor, Science 297 (5579)

(2002) 259263.

[21] S.J. Hong, T.M. Dawson, V.L. Dawson, Nuclear and mitochondrial

conversations in cell death: PARP-1 and AIF signaling, Trends Phar-

macol. Sci. 25 (5) (2004) 259264.

[22] Z.Q. Wang, et al., Mice lacking ADPRT and poly(ADP-ribosyl)ation

develop normally but are susceptible to skin disease, Genes Dev.

9 (5) (1995) 509520.

[23] J. Menissier-de Murcia, et al., Requirement of poly(ADP-

ribose)polymerase in recovery from DNA damage in mice and in

cells, Proc. Natl. Acad. Sci. U.S.A. 94 (1997) 73037307.

[24] M. Masutani, et al., The response of Parp knockout mice against

DNA damaging agents, Muta Res. 462 (23) (2000) 159166.

[25] J. Menissier-de Murcia, et al., Functional interaction between PARP-1

and PARP-2 in chromosome stability and embryonic development in

mouse, Embo. J. 22 (9) (2003) 22552263.

[26] R. Beneke, et al., DNA excision repair and DNA damage-induced

apoptosis are linked to poly(ADP-ribosyl)ation but have different

requirements for p53, Mol. Cell Biol. 20 (18) (2000) 66956703.

[27] F. Dantzer, et al., Base excision repair is impaired in mammalian

cells lacking poly(ADP-ribose) polymerase-1, Biochemistry 39 (25)

(2000) 75597569.

[28] C. Trucco, et al., DNA repair defect in poly(ADP-ribose)

polymerase-deficient cell lines, Nucleic Acids Res. 26 (11) (1998)

26442649.

[29] Y. Shiloh, ATM and related protein kinases: safeguarding genome

integrity, Nat. Rev. Cancer 3 (3) (2003) 155168.

[30] C. Barlow, et al., Atm-deficient mice: a paradigm of ataxia telang-

iectasia, Cell 86 (1) (1996) 159171.[31] A. Barzilai, G. Rotman, Y. Shiloh, ATM deficiency and oxidative

stress: a new dimension of defective response to DNA damage, DNA

Repair (Amst) 1 (1) (2002) 325.

[32] M.S. Henrie, et al., Lethality in PARP-1/Ku80 double mutant mice

reveals physiological synergy during early embryogenesis, DNA Re-

pair (Amst) 2 (2) (2003) 151158.

[33] J. Sekiguchi, et al., Genetic interactions between ATM and the non-

homologous endjoining factors in genomic stability and development,

Proc. Natl. Acad. Sci. U.S.A. 98 (6) (2001) 32433248.

[34] G. de Murcia, A. Huletsky, G.G. Poirier, Modulation of chromatin

structure by poly(ADP-ribosyl)ation, Biochem. Cell Biol. 66 (6)

(1988) 626635.

[35] C.J. Bakkenist, M.B. Kastan, DNA damage activates ATM through

intermolecular autophosphorylation and dimer dissociation, Nature

421 (6922) (2003) 499506.[36] O. Fernandez-Capetillo, A. Celeste, A. Nussenzweig, Focusing on

foci: H2AX and the recruitment of DNA-damage response factors,

Cell Cycle 2 (5) (2003) 426427.

[37] K.W. Caldecott, XRCC1 and DNA strand break repair, DNA Repair

(Amst) 2 (9) (2003) 955969.

[38] J. Menisser-de Murcia, et al., Early embryonic lethality in PARP-1

Atm double-mutant mice suggests a functional synergy in cell pro-

liferation during development, Mol. Cell Biol. 21 (5) (2001) 1828

1832.

Documents

parp 1 e 2