Ageing and PARP
Section snippets
Ageing and the maintenance of DNA integrity and stability
Ageing is an almost universal biological phenomenon in multicellular organisms and has been defined as the time-dependent general decline in physiological function of an organism, associated with a progressively increasing risk of morbidity and mortality [1]. At the cellular level, the ageing process is characterised by the accumulation of molecular damage in biological macromolecules including DNA, proteins and lipids. Such damage will impair macromolecular function, which may have an impact
Poly(ADP-ribosyl)ation of proteins
Poly(ADP-ribosyl)ation is a posttranslational modification of proteins that was first described in the 1960s [3]. This modification is carried out by a family of enzymes called poly(ADP-ribose) polymerases (PARPs) [4]. One of the remarkable features of poly(ADP-ribosyl)ation is its occurrence as an immediate cellular response to genotoxic insults induced by ionising radiation, alkylating agents and oxidative stress (for review see [5]). In such conditions, poly(ADP-ribosyl)ation is catalysed
Role of PARPs in DNA repair pathways
During the process of base-excision repair, damaged bases are recognised by specific DNA glycosylases and cut out and the affected DNA-strand is incised AP endonuclease at the resulting abasic site, thus creating a DNA single strand break [19]. Two members of the PARP family, i.e. PARP-1 and PARP-2, are known to be activated by DNA-strand breaks. Upon binding and activation, they are thought to regulate the accessibility of the DNA repair site to other repair enzymes. PARP-1 and PARP-2 knockout
Poly(ADP-ribosyl)ation as a function of mammalian life span
Over a decade ago, we reported a correlation between cellular poly(ADP-ribose) formation capacity (largely due to PARP-1 activity) and the life span of mammalian species in permeabilised mononuclear blood cells (MNC) from 13 mammalian species [40]. The difference between the shortest and the longest-lived species tested (rat and human, respectively) was five-fold. This difference was not due to differential PARP-1 protein expression, suggesting that some qualitative differences in PARP-1 might
Additionals links between poly(ADP-ribosyl)ation and ageing/longevity
As stated above, PARPs are also implicated in the ageing process, independent of their function in DNA repair. The relevant mechanisms are telomere regulation, interaction with WRN, and involvement in mitosis.
Telomeres play an important role in defining the replicative potential (“life span”) of human cells in culture [46]. Normal somatic cells isolated from the human body, such as fibroblasts, are able to undergo a limited number of cell divisions before they reach the so-called “Hayflick
Conclusions and perspective
PARPs are important components in the cellular responses to various kinds of insults to genomic DNA, including oxidative DNA damage, telomere erosion, or improper segregation of chromosomes. Collectively this may keep ageing-related cellular dysfunction, including carcinogenesis and cell loss, in check (Fig. 1). Here we have summarised several independent lines of evidence that are all supporting an involvement of members of the PARP family in retarding the ageing process. First, as genotoxic
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft (“Forschergruppe 434 Oligosaccharid- und DNA-Chips – Analyse sekundärer Genprodukte”, Sub-project 11, Bu698-4/1) and the EU Commission (Specific Targeted Research Project FOOD-CT-2003-506850 “Nutritional zinc, oxidative stress and immunosenescence: biochemical, genetic and lifestyle implications for healthy ageing [ZINCAGE]”) is gratefully acknowledged.
References (63)
- et al.
Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme
Biochem Biophys Res Commun
(1963) - et al.
Mode of action of poly(ADP-ribose) glycohydrolase
Biochim Biophys Acta
(1994) - et al.
PARP-2, a novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase
J Biol Chem
(1999) - et al.
Poly(ADP-ribose) polymerase null mouse cells synthesize ADP-ribose polymers
J Biol Chem
(1998) - et al.
TANK2, a new TRF1-associated poly(ADP-ribose) polymerase, causes rapid induction of cell death upon overexpression
J Biol Chem
(2001) - et al.
The human Rap1 protein complex and modulation of telomere length
J Biol Chem
(2004) - et al.
Tankyrase is a golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles
J Biol Chem
(2000) - et al.
Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins
J Biol Chem
(2000) - et al.
Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions
J Biol Chem
(1998) - et al.
Purification and analysis of a factor which suppresses nick-induced transcription by RNA polymerase II and its identity with poly(ADP-ribose) polymerase
J Biol Chem
(1983)
Stimulation of the DNA-dependent protein kinase by poly(ADP-ribose) polymerase
J Biol Chem
Identification and biochemical characterization of a Werner's syndrome protein complex with Ku70/80 and poly(ADP-ribose) polymerase-1
J Biol Chem
Role of DNA-PK in the cellular response to DNA double-strand breaks
DNA Repair
Comparative characterisation of poly(ADP-ribose) polymerase-1 from two mammalian species with different life span
Exp Gerontol
Oxidative stress shortens telomeres
Trends Biochem Sci
Telomeres do D-loop-T-loop
Cell
Mammalian telomeres end in a large duplex loop
Cell
Identification of a specific telomere terminal transferase activity in tetrahymena extracts
Cell
Genetic cooperation between the Werner syndrome protein and poly(ADP-ribose) polymerase-1 in preventing chromatid breaks, complex chromosomal rearrangements, and cancer in mice
Am J Pathol
The Werner syndrome protein stimulates DNA polymerase beta strand displacement synthesis via its helicase activity
J Biol Chem
The N-terminal domain of the large subunit of human replication protein A binds to Werner syndrome protein and stimulates helicase activity
Mech Ageing Dev
Physical and functional interaction of the Werner syndrome protein with poly-ADP ribosyl transferase
FEBS Lett
Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases
J Biol Chem
Centromere proteins Cenpa, Cenpb, and Bub3 interact with poly(ADP-ribose) polymerase-1 protein and are poly(ADP-ribosyl)ated
J Biol Chem
The biology of aging
Mt Sinai J Med
Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function
Ann NY Acad Sci
The PARP superfamily
Bioessays
Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse
EMBO J
Involvement of poly(ADP-Ribose) polymerase 1 and poly(ADP-ribosyl)ation in regulation of centrosome function
Mol Cell Biol
PARP-3 localizes preferentially to the daughter centriole and interferes with the G1/S cell cycle progression
J Cell Sci
Cited by (54)
Arsenite-induced ROS/RNS generation causes zinc loss and inhibits the activity of poly(ADP-ribose) polymerase-1
2013, Free Radical Biology and MedicineCitation Excerpt :The PARP family of proteins include 17 different members and PARP-1 activity accounts for about 90% of the total cellular poly(ADP-ribose) formation [1,2]. Activation of PARP-1 occurs as an immediate cellular response to DNA strand breaks, which can be induced by ionizing radiation, alkylating agents, or oxidative stress [1,3]. PARP-1 comprises three functional domains [4].
Protein biomarkers for in vitro testing of toxicology
2012, Mutation Research - Genetic Toxicology and Environmental MutagenesisCitation Excerpt :Because cancer is always related to differentiation [41] (which is mechanistically related to developmental toxicity), the rapid development of new technologies in epigenomics [42] has raised hopes for a new class of biomarkers and therapeutic targets, in particular those centered around enzymes which directly affect chromatin structure like DNA methyltransferases [43], histone deacetylases (HDAC) [44] and sirtuins [45], and around one key enzyme which is closely related due to competition for substrates, in particular NAD+, i.e. poly-ADP-ribose polymerase 1 (PARP-1) [46]. Inhibitors or activators of all these enzymes are under development as anti-cancer drugs, while sirtuins and PARP-1 have intriguing roles in ageing and PARP-1 is moreover one of the key biomarkers for apoptosis [47,48]. Due to the relation to the substrates NAD+ and S-adenosylmethionine, these enzymes are not only very flexible sensors of energy metabolism, but as in the case of PARP-1, are extremely efficacious effectors by catalyzing a post-translational modification which rapidly depletes cellular NAD+.
Gender and the regulation of longevity: Implications for autoimmunity
2012, Autoimmunity ReviewsInterdependent genotoxic mechanisms of monomethylarsonous acid: Role of ROS-induced DNA damage and poly(ADP-ribose) polymerase-1 inhibition in the malignant transformation of urothelial cells
2011, Toxicology and Applied PharmacologyCitation Excerpt :There are multiple DNA repair enzymes involved in the repair of damaged DNA; however, poly(ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme involved in the initiation of base excision repair following oxidative DNA damage, such as DNA single-strand breaks (Caldecott, 2007; Gradwohl et al., 1990). Despite the existence of 17 different members of PARP, PARP-1 constitutes 90% of the overall cellular poly(APP-ribosyl)ation activity (Burkle et al., 2005; Qin et al., 2008; Schreiber et al., 2006). PARP-1 specifically binds to DNA strand breaks in a zinc-dependent manner.
Overexpression of PaParp encoding the poly(ADP-ribose) polymerase of Podospora anserina affects organismal aging
2011, Mechanisms of Ageing and DevelopmentCitation Excerpt :Loss of information stored in DNA will result in functional deficiencies and thereby contribute to the breakdown of cellular integrity. The impact of PARP activity on these processes has been intensively studied in particular in mammalian systems (Beneke and Bürkle, 2007; Bürkle et al., 2005; Muiras and Bürkle, 2000). However, due the number of individual PARP family members and their diverse roles (18 have been reported for Homo sapiens by Amé et al., 2004) and due to the complex organization of mammalian species many questions about the role of PARP in aging and age-related changes remain to be elaborated.