Conceptual Developments in the Causes of Cockayne Syndrome

Home , Base excision repair, ERCC1, ERCC8 (gene), XPA

Mechanisms of Ageing and Development 134 (2013) 284–290

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Mechanisms of Ageing and Development

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Conceptual developments in the causes of Cockayne syndrome

a, b a c,1

James E. Cleaver *, Vladimir Bezrookove , Ingrid Revet , Eric J. Huang

Department of Dermatology, University of California San Francisco, 2340 Sutter Street, San Francisco, CA 94143, United States

Center for Melanoma Research & Treatment, California Paciﬁc Medical Center & Research Institute, San Francisco, CA, United States

Department of Pathology, University of California San Francisco, San Francisco, CA 94143, United States

A R T I C L E I N F O A B S T R A C T

Article history: Cockayne syndrome is an autosomal recessive disease that covers a wide range of symptoms, from mild

Available online 18 February 2013

photosensitivity to severe neonatal lethal disorder. The pathology of Cockayne syndrome may be caused

by several mechanisms such as a DNA repair deﬁciency, transcription dysregulation, altered redox

Keywords: balance and mitochondrial dysfunction. Conceivably each of these mechanisms participates during a

Ultraviolet light

different stage in life of a Cockayne syndrome patient. Endogenous reactive oxygen is considered as an

Reactive oxygen

ultimate cause of DNA damage that contributes to Cockayne syndrome pathology. Here we demonstrate

Mitochondria

that mitochondrial reactive oxygen does not cause detectable nuclear DNA damage. This observation

Transcription coupled repair

implies that a signiﬁcant component of Cockayne syndrome pathology may be due to abnormal

Neurodegeneration

mitochondrial function independent of nuclear DNA damage. The source of nuclear DNA damage to

central nervous system tissue most likely occurs from extrinsic neurotransmitter signaling.

1. Cockayne syndrome: genes and transcription coupled repair recover has been less well investigated and may be secondary to

the impact of CS mutations on RNA transcription.

Cockayne syndrome (CS) is a neurocutaneous disorder named The discovery that repair was more rapid in transcribed genes,

in the 1950s after a dermatologist who practiced in the early and regulated by CS genes, was based on a series of direct

decades of the 20th century (Marie et al., 1958). Cellular studies in measurements of photoproduct excision in selected genes (Mans-

the 1970s discovered that CS ﬁbroblasts were sensitive to killing by bridge and Hanawalt, 1983; Venema et al., 1990). Repair in the

ultraviolet (UV) light (Schmickel et al., 1977), ushering the alpha satellite sequence, a major repeat sequence, was found to be

subsequent avalanche of studies on the molecular characterization less efﬁcient than in the rest of the genome (Zolan et al., 1982).

of this disorder (Table 1). The UV sensitivity was shown to be Highly expressed genes (dhfr, p53) were more rapidly repaired

associated with a failure of CS cells to recover RNA and DNA than the remainder of the genome (Bohr et al., 1985; Mellon et al.,

synthesis after UV damage (Lehmann et al., 1979; Cleaver, 1982). 1986; Evans et al., 1993). Repair was faster in the transcribed

This property was used to demonstrate that there were two genes strand than in the nontranscribed strand (Bohr et al., 1985; Mellon

uniquely involved in the disease, named CSA and CSB (also ERCC8, et al., 1987). Detailed studies of photoproduct repair in one gene,

ERCC6 respectively) and that there was overlap with another UV PGK1, showed wide variation in repair rates between the

sensitive disease xeroderma pigmentosum (XP) (Lehmann, 1982). transcribed and nontranscribed strands, as well as additional

The failure of RNA synthesis to recover after irradiation was found variations depending on nucleotide position, transcription start

to correlate with loss of rapid excision repair subsequently site and the binding of transcription factors (Pfeifer et al., 1991;

discovered in actively transcribed genes (transcription coupled Gao et al., 1994).

repair, TCR (Mansbridge and Hanawalt, 1983; Venema et al., 1990; The CSB protein has a number of properties that can be

Sancar, 1996; Wood, 1997)). The arrest of RNA Pol II at a damaged demonstrated in vitro. It has a nucleotide binding site and acts as a

site is now recognized as the initiating signal for TCR (Fig. 1) DNA-dependent ATPase (Selby and Sancar, 1997; Citterio et al.,

(Lindsey-Boltz and Sancar, 2007). The failure of DNA synthesis to 1998). The CSB protein can actively wrap the DNA (Beerens et al.,

2005) and has strand-annealing capacity (Muftuoglu et al., 2006).

CSB associates with PCNA that may be the mechanism by which

CS-B cells have reduced recovery of DNA synthesis (Balajee et al.,

* Corresponding author at: Dermatology and Pharmaceutical Chemistry,

Department of Dermatology, Box 0808, Room N431, University of California San 1999). How many of these properties are directly related to the

Francisco, San Francisco, CA 94143-0808, United States. Tel.: +1 415 476 4563; clinical disorders remains to be established. Proteins in vitro, may

fax: +1 415 476 8218.

reveal properties that are normally suppressed in vivo or lack

E-mail addresses: [email protected] (J.E. Cleaver), [email protected]

necessary modiﬁcations such as phosphorylation, polyADP-ribo-

(V. Bezrookove), [email protected] (E.J. Huang).

1 sylation or ubiquitylation that occur in vivo.

Tel.: +1 415 476 8525.

J.E. Cleaver et al. / Mechanisms of Ageing and Development 134 (2013) 284–290 285

Table 1

Cellular and in vivo consequences of Cockayne mutations.

CSA (ERCC8) CSB (ERCC6) UVSSA

Clinical features

Growth failure Yes Yes No

Aging Yes Yes No

Neurodegeneration Yes Yes No

Skin photosensitivity Yes Yes Yes

Cellular features

UV sensitivity Yes Yes Yes

a a

ROS sensitivity Yes Yes No

Transcription coupled repair Reduced Reduced Reduced

RNA synthesis recovery Reduced Reduced Reduced

Although most reports describe CS-A cells as being sensitive to exogenous

Fig. 1. Nuclear and mitochondrial functions of the RNA Pol II cofactors CSA, CSB,

reactive oxygen, two reports found human and mouse CS-A cells less sensitive than

UVSSA and USP7 that regulate transcription of damaged DNA and facilitate

CS-B cells (de Waard et al., 2004; D’Errico et al., 2007) and one had normal cleavage

enhanced repair of the transcribed strand. CSA and CSB are also located in the

of 8-OH-Gua in vitro whereas CS-B cells lacked this activity (D’Errico et al., 2007).

mitochondria where they play a role in autophagy and electron transport. Nuclear

UVSSA cells have been less intensively investigated but two UV patients with either

functions regulate gene transcription and responses to exogenous stresses.

a CSA or a UVSSA mutation showed a normal response to ROS (Nardo et al., 2009;

Mutations in mitochondrial functions may cause accumulation of damaged

Spivak and Hanawalt, 2006).

mitochondria from endogenous oxidative stress that may lead to

neurodegeneration (Wallace, 2005; Cleaver, 2012).

Once the association of transcription with repair was estab- (Graham et al., 2001), and the mild photosensitive UV syndrome

lished by direct measurements in a small number of genes, (Fujiwara et al., 1981; Itoh et al., 1995).

followed by the discovery of the central role of the transcription COFS syndrome is also an autosomal, recessively inherited and

factor TFIIH in nucleotide excision repair (NER) (Schaeffer et al., rapidly progressive, neurologic disorder. The disease leads to brain

1993), little attention was devoted to further direct measurement microcephaly and atrophy with calciﬁcations, cataracts, micro-

of rates of repair in speciﬁc genes and different functional states of cornea, optic atrophy, progressive joint contractures, and growth

the genome. There has yet to be a whole genome assessment of failure. COFS appears to be a particularly severe developmental and

rates of repair. Whether additional levels of regulation beyond neurological disease with mutations in CSB, XPG, XPD or ERCC1

transcription can affect repair remains unanswered. Recent whole (Graham et al., 2001; Niedernhofer et al., 2006; Jaspers et al., 2007;

genome sequencing studies have demonstrated that most of the Laugel et al., 2008). All of these genes are associated with

genome is transcribed into RNA at some stage, raising questions of transcription regulation either as cofactors of RNA pol II or

the deﬁnition of TCR and its restriction to protein-coding regions of components of transcription factor TFIIH.

the genome. Some UV-sensitive patients, deﬁned as the UV syndrome, lack

the neurological pathology of CS but their cells are UV sensitive and

defective in TCR (Table 1) (Fujiwara et al., 1981; Cleaver et al., 1992;

2. Clinical complexity of CS I, II, UVS, COFS Itoh et al., 1995). Some of these represent mild manifestations of

mutations in CSA (Nardo et al., 2009; Fei and Che, 2012) and CSB,

CS is an autosomal recessive disease in which the clinical remarkably one resulting in no detectable CSB protein (Horibata

disorders can be classiﬁed in three general areas of growth failure, et al., 2004). Others appear to be genuinely different (Itoh et al., 1994,

pathological aging and neurodegeneration (Nance and Berry, 1992; 1995). A gene identiﬁed as mutated in several UV patients encodes

Weidenheim et al., 2009). Symptoms involve many organ systems another RNA pol II cofactor named UVSSA (Fig. 1) (Nakazawa et al.,

leading to cachectic dwarﬁsm, retinopathy, microcephaly, deafness, 2012; Schwertman et al., 2012; Zhang et al., 2012).

neural defects, skin photosensitivity and retardation of growth and The wide range of severity in CS, COFS and UV patients belies

development. CS patients are sun sensitive but do not develop the essential identity of their defects in TCR. Correlations between

cancers, setting this disease apart from XP which shows high levels the clinical disorder, the functional deﬁciency in TCR and the sites

of skin cancer associated with failure in global nucleotide excision of mutations in CSA, CSB and UVSSA have yet to be made and there

repair (NER) (Cleaver, 2005). The absence of cancer has been is no genotype–phenotype correlation at present (Laugel et al.,

attributed to a high level of apoptosis caused by transcription arrest 2010). The absence of neurological disease in UV patients,

after UV exposure that eliminates premalignant cells (Ljungman and however, implies that the defects in TCR are only correlated

Zhang, 1996; Balajee et al., 2000; Proietti De Santis et al., 2002). directly with the skin photosensitivity and may not be the cause of

Subsequent work, however, using both growing and conﬂuent developmental and neurological symptoms (Cleaver, 2012). The

ﬁbroblasts has shown that apoptosis is caused more directly by DNA cause of these symptoms must be sought in other mechanisms. The

replication on damaged templates (Carvalho et al., 2003; da Costa default explanation of neurodegeneration in CS has frequently

et al., 2008). Normal, XP-C and TTD cells were more resistant to been sensitivity to endogenous reactive oxygen species (ROS),

apoptosis when conﬂuent than when in exponential growth; CS cells often thought to be of mitochondrial origin (Youle and van der

had similar levels of apoptosis in both states, at levels that were Bliek, 2012). This explanation needs direct examination, although

between the conﬂuent and growing levels in XP-C cells (Carvalho it has credence because only CS-A and CS-B cells and mice are

et al., 2003; da Costa et al., 2008). The reason for the absence of skin sensitive to ROS, but UV cells of various genotypes are not

cancer in CS patients therefore still remains an open question. (Table 1). We will address the issue of causes of CS pathology by

Cockayne syndrome was initially classiﬁed in several categories asking: is CS (a) a repair syndrome, (b) a transcription syndrome, or

according to severity of the symptoms, mainly as CS types I and II (c) a mitochondrial and ROS syndrome.

(Nance and Berry, 1992) but these clinical classiﬁcations do not

correspond to the genes CSA and CSB. Two other disorders can be 3. Is Cockayne syndrome a repair syndrome?

included as CS-related because of their common biochemical

deﬁciency in TCR and increased UV sensitivity: the severe neonatal CSA, CSB and UVSSA are cofactors of RNA Pol II that are involved

lethal disorder cerebro-oculo-facio-skeletal syndrome (COFS) in a deubiquitin pathway when the enzyme is blocked by

286 J.E. Cleaver et al. / Mechanisms of Ageing and Development 134 (2013) 284–290

photoproducts or other possible obstructions to transcription such transcription on conformationally abnormal template structures;

as natural pause sites due to refractory sequences or secondary in damaged cells there will be transcription blocking lesions that

structures in the template strand (Anindya et al., 2010; Cleaver, will affect both constitutively transcribed genes and those induced

2012). CSA, CSB and UVSSA coordinate a deubiquitin pathway that (e.g., fos). A failure of transcription to recover after UV irradiation

results in the displacement of RNA Pol II from transcription blocking was one of the earliest biomarkers of the CS genotype (Lehmann,

lesions (Anindya et al., 2010; Cleaver, 2012). CSA recruits UVSSA 1982). This failure of recovery represents a global down-regulation

after UV damage to form a complex with USP7 (ubiquitin speciﬁc of house-keeping genes due to the lack of recruitment of RNA pol II

protease 7) that removes ubiquitin, stabilizes the ERCC6/RNA Pol II- and basal transcription factors to their promoters (Proietti-De-

complex (Boom et al., 2004), and restores the hypophosphorylated Santis et al., 2006). Oxidative stress similarly causes a wide-spread

form of RNA Pol II (Fei and Che, 2012). After RNA Pol II displacement, downregulation of transcription, involving genes for DNA repair,

as a result of deubiquitylation, the transcription-stalling damage is transcription, signal transduction and ribosomal function (Kyng

m/m /

removed, allowing transcription to resume. Excision of the stalling et al., 2003). In vivo we found that preweaned Csb .Xpc mice

lesion involves the later stages in the NER mechanism. The global showed a speciﬁc effect on the transcription of myelin by

recognition proteins DDB2 and XPC are not needed and excision oligodendroglia leading to a dysmyelination phenotype (Revet

proceeds with XPA (DNA damage binding), TFIIH (unwinding), XPG et al., 2012). Oligodendroglia are major players in neurodegenera-

and XPF/ERCC1 (excision nucleases) tion in ALS (Lee et al., 2012).

Defective repair of UV damage in CS cells appears to be speciﬁc One mechanism by which CSB regulates transcription is by

for cyclobutane dimers, with normal repair for [6–4] photopro- competing with p53 in regulating damage inducible genes

ducts (Barrett et al., 1991; Parris and Kraemer, 1993) and DNA (Proietti-De-Santis et al., 2006; Filippi et al., 2008; Frontini and

single strand breaks (Spivak and Hanawalt, 2006). One explanation Proietti-De-Santis, 2009; Lake et al., 2011). CSA and CSB both

for this speciﬁcity may be kinetic: rapid recognition and excision of mediate the transcription response to hypoxia via association with

[6–4] photoproducts by the global genome pathway (GGR) may p53 (Filippi et al., 2008) (D’Errico et al., 2007). CSB and p53 directly

remove them before signiﬁcant transcription arrest occurs, leaving interact, such that p53 association with chromatin is enhanced by

cyclobutane dimers to be the arresting culprits. This kinetic CSB at low p53 concentrations. In contrast, at high concentrations

explanation may also apply to the mouse strains in which Cs-b p53 excludes CSB (Lake et al., 2011).

mutant mice were crossed with Xp-c or Xp-a mutants (van der A genome wide array study demonstrated that CSB deﬁciency

Pluijm et al., 2006; Laposa et al., 2007; Revet et al., 2012). The has similar effects on a panoply of genes as had inhibitors of

additional repair deﬁciencies in the double knockout mice result in histone deacetylase, DNA methylation, and poly(ADP-ribose)-

loss of excision capacity of a broad range of substrates, thereby polymerase, and suggested a general role for CSB protein in

increasing the number of transcription blocking lesions. maintenance and remodeling of chromatin structure (Newman

Strong evidence for a repair-dependent mechanism underlying et al., 2006). Chromatin remodeling involves ATP hydrolysis by CSB

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CS comes from a conditional mouse mutant in which a Csb and subsequent conformational change in CSB structure that

mouse was crossed with a mouse in which an exon in the Xpa gene overcomes an inhibitory effect of its N terminus (Lake et al., 2010,

was ﬂanked with Cre sites allowing elimination of Xpa in neurons 2011). In one of our own studies we compared differential gene

m/m

of Csb mice post weaning (Jaarsma et al., 2011). This strain expression in CSB, child and mother pairs, and found very limited

showed progressive neuronal deﬁciencies suggesting, in the differences in base-line gene expression (Cleaver et al., 2007);

authors’ words ‘‘. . .that adult neurons in rodents are vulnerable dysregulation was suggestive for p21, collagen XV and latrophilin

to endogenous DNA lesions when deﬁcient in both NER and TCR, but we were unable conﬁrm that these were a direct consequence

but are able to cope with these lesions when either the TCR or NER of CSB mutation in CS-B ﬁbroblasts complemented with CSB cDNA

pathway are defective. . .’’ (Jaarsma et al., 2011). This elegant work (Revet et al., 2012).

demonstrates the importance of DNA repair, but as emphasized

further in this review, does not identify the origin or nature of 5. Is Cockayne syndrome a mitochondrial and ROS syndrome?

endogenous lesions.

Consistent with a repair mechanism for CS, DNA adducts of An unanticipated recent discovery has been the localization of

oxidative origin have been identiﬁed in human and mouse tissues: CSA and CSB in the mitochondria, and their involvement in repair

cyclodA accumulated in tissues of Cs-b mice (Brooks, 2007; Kirkali of mitochondrial DNA damage and in the electron transport chain

et al., 2009); G[8–5m]T, accumulated in healthy human and mouse (Aamann et al., 2010; Kamenisch et al., 2010; Pascucci et al., 2012;

tissues and was elevated in human XP-A and Ercc1 mice (Wang Scheibye-Knudsen et al., 2012; Sykora et al., 2012). Mutations in

et al., 2012b). Interestingly, the latter study did not detect the kinds CSA and CSB consequently inﬂuence the redox balance and

of single base lesions that would be typical of ROS damage, which mediate hypersensitivity to oxidative agents (Pascucci et al., 2012).

m/m

could be due to their rapid repair by endogenous glycosylases Mitochondrial content is increased in Csb mouse cells due to

(Wang et al., 2012b). In vitro studies using plasmids with deﬁned reduced autophagy and the residual mitochondria are highly

lesions showed that CS cells repair apurinic sites and single strand abnormal resulting in increased free radical production (Fig. 2)

breaks normally but are defective at repair of oxidized bases (Scheibye-Knudsen et al., 2012). The failure of autophagy has been

(Spivak and Hanawalt, 2006). linked to neurodegeneration (Komatsu et al., 2006). The observa-

m/m

In these studies the question remains concerning the sources of tion of speciﬁc abnormalities in the Purkinje cells of Csb mice

DNA damage in vivo and whether they are intrinsic to neuronal (Laposa et al., 2007) may be related to this mitochondrial function.

cells or arise from neurotransmitter signaling or extrinsic The accumulation of damaged mitochondria in Purkinje cells can

circulating agents. block the numerous branching extensions that establish up to

150,000 synaptic neuronal connections for each Purkinje cell

4. Is Cockayne syndrome a transcription syndrome? (Girard et al., 2012) leading to Purkinje cell degeneration (Laposa

et al., 2007). The observation of mitochondrial functions for CSA

The association of CSA and B proteins with RNA Pol II clearly and CSB puts Cockayne syndrome into context with many other

points to their role in transcription regulation. Such regulation may human neurodegenerative diseases that have abnormal mitochon-

occur in ostensibly undamaged cells or after deliberate exposure to drial functions, some caused by mutations in mitochondrial DNA

damaging agents. In undamaged cells CS proteins may affect (Lax et al., 2011; Lenzken et al., 2011).

J.E. Cleaver et al. / Mechanisms of Ageing and Development 134 (2013) 284–290 287

Fig. 3. Increased reactive oxygen caused by the mitochondrial complex I inhibitor

rotenone causes cell death but no detectable DNA damage. Cells harvested 4 h after

start of exposure to UVB (120 J m ; survival 40% wt, 3% CS-B), and rotenone (Rot,

200 nM; survival 30% wt, 20%CS-B).

evidence for nuclear DNA damage from mitochondrial leakage is

m/m /

Fig. 2. Electron microscopy of mitochondria in Csb .Xpc mice and slight in contrast to damage from external sources of ROS (Pascucci

+/m /

heterozygous littermate Csb .Xpc from previous studies into

et al., 2012).

oligodendrocyte differentiation in these mice (Revet et al., 2012).

We recently addressed this question of whether nuclear DNA

damage can result from mitochondrial ROS in a pilot experiment

P53 also accumulates in the mitochondrial matrix under using rotenone, an inhibitor of mitochondrial complex I that causes

oxidative stress and triggers mitochondrial permeability transition autophagy and increased ROS (Wallace, 2005). We exposed CSB

pore (PTP) opening by physical interaction with the PTP regulator and wild type ﬁbroblasts to rotenone, and conﬁrmed that rotenone

cyclophilin D (CypD) that then leads to necrosis (Vaseva et al., increased endogenous ROS using Mitosox ﬂuorescent dye. DNA

2012). The interaction between CSB and p53 in nuclear gene damage was measured by gH2Ax phosphorylation (gH2Ax) that

expression (Proietti-De-Santis et al., 2006; Filippi et al., 2008; can result from activation of the ATM and ATR damage responsive

Frontini and Proietti-De-Santis, 2009; Lake et al., 2011) might also kinases by ROS (Guo et al., 2010) and a range of other agents

occur in the mitochondria and be involved in necrosis (Vaseva including UV and ionizing radiation (Revet et al., 2011) and

et al., 2012) and autophagy (Scheibye-Knudsen et al., 2012). replication arrest (de Feraudy et al., 2007). Increased gH2Ax was

Mitochondria are deﬁcient in nucleotide excision repair of both detectable from UVB, which causes direct DNA damage and

cyclobutane dimers and [6–4] photoproducts (Clayton et al., 1974; intracellular ROS (Fig. 3). But there was no increase in gH2Ax from

Pascucci et al., 1997) but competent in base excision repair rotenone treatment, suggesting there was no nuclear DNA damage

(Stevsner et al., 2008; Sykora et al., 2012). CSB appears to stimulate (Fig. 3). This result clearly deserves more study, that we are

the activity of nuclear and mitochondrial 8-oxo-G glycosylase, but carrying out using an isogenic pair of CS-B and CS-B corrected cell

not thymine or uracil glycosylases, and interacts with PARP-1 and lines, and the outcome will be reported later. The corollary is that

AP endonuclease (Stevsner et al., 2008). The accumulation of single nuclear DNA damage in vivo is more likely to result from

base damage in vivo would be expected if repair of 8-oxo-dG exogenous exposures from agents in the general circulation than

glycosylase was defective but such evidence is at present limited mitochondrial leakage. Identifying these source(s) will be critical

(Wang et al., 2012b). in devising rational strategies for therapeutic intervention.

If mitochondrial ROS is effectively quenched in the cytoplasm,

6. Endogenous reactive oxygen and DNA damage there is likely to be an accumulation of oxidized cytoplasmic

proteins (Reyes et al., 2012) that could become the centers for

There is ample evidence for formation of oxidative DNA adducts protein misfolding. If such protein misfolding were to occur in CS,

in vivo from endogenous ROS, from a variety of sources (Brooks, this would bring CS into the wider fold of neurodegerative diseases

2007; Kirkali et al., 2009) (Wang et al., 2012b). Potential sources that have a common mechanism of misfolded proteins that are

include the inﬂammatory (innate immune) response or oxidative propagated as prions (Prusiner, 2012).

burst from macrophages or neutrophils in peripheral blood,

involving enzymes such as p450 oxidase and NADPH oxidase. 7. Role of TCR and CS gene expression in cancer

Glial cells in the brain that originate in the myeloid lineage and

which are increased in CS brain tissue could similarly be a source of The capacity to sequence whole genomes has recently been

oxidative damage (Dedon and Tannenbaum, 2004; Graeber, 2010; applied to human cancers producing considerable insight into the

Petersen et al., 2012). Nitric oxide, a neurotransmitter, has been mechanism of carcinogenesis from chemicals or radiations. The

shown to damage mitochondrial DNA (Druzhyna et al., 2005). genomic sequences of melanoma (Pleasance et al., 2010a) and lung

Overstimulation of neuronal NMDA-type glutamate receptors cancer (Pleasance et al., 2010b) showed signature mutations

activated NADPH oxidase (neuronal NOX2) and generated corresponding to solar radiation or chemical exposure, respective-

superoxide that damaged adjacent cells and induced apoptosis, ly. Both tumors showed evidence for reduced mutagenesis due to

(Reyes et al., 2012). Glutamate also stimulated the induction of TCR of the transcribed strands of expressed genes and a more

apurinic endonuclease 1, a major repair enzyme of oxidative DNA general expression-linked repair operating on both strands. The

damage (Yang et al., 2010). latter, expression-linked repair may correspond to repaired

A frequent comment in discussion of the sources of ROS damage regions originally identiﬁed in XP-C cells that appeared consider-

to DNA, especially in the context of neurodegeneration, is to blame ably larger than individual genes (Mansbridge and Hanawalt,

mitochondrial leakage of byproducts of oxidative phosphorylation 1983; Karentz and Cleaver, 1986; Kantor et al., 1990). Despite the

(Hoeijmakers, 2001; Barnes and Lindahl, 2004; Wallace, 2005) or action of TCR, many driver mutations occurred in actively

mitochondrial autophagy (Koren and Kimchi, 2012). This raises the expressed genes, an observation that raises the following dilemma.

question of whether mitochondrial leakage of ROS can result in If TCR reduces the mutation rates in tumor-speciﬁc genes as

nuclear DNA damage, given the cellular content of antioxidant these studies indicate, then one might expect that deﬁciencies in

enzymes such as catalase and superoxide dismutase and numerous TCR should increase the mutation rates and hence increase cancer

cytoplasmic targets for oxidants that can absorb these byproducts. incidence, but they do not. Reduced expression of CSA and CSB has

Mitochondrial DNA damage has clearly been demonstrated but been observed in primary breast cancers relative to normal tissue,

288 J.E. Cleaver et al. / Mechanisms of Ageing and Development 134 (2013) 284–290

Anindya, R., Mari, P.O., Kristensen, U., Kool, H., Giglia-Mari, G., Mullenders, L.H.,

suggesting a downregulation of TCR occurs early in carcinogenesis

Fousteri, M., Vermeulen, W., Egly, J.M., Svejstrup, J.Q., 2010. A ubiquitin-binding

(Latimer et al., 2010). But the opposite is the case with inherited

domain in Cockayne syndrome B required for transcription-coupled nucleotide

mutations in TCR. Deﬁciencies in global repair of non-transcribed excision repair. Molecular Cell 38, 637–648.

Balajee, A.S., DeSantis, L.P., Brosh Jr., R.M., Selzer, R., Bohr, V.A., 2000. Role of the

regions of the genome correlate with increased cancer incidence in

ATPase domain of the Cockayne syndrome group B protein in UV induced

XP patients, especially in XP-C patients who lack global repair of

apoptosis. Oncogene 19, 477–489.

nontranscribed regions but speciﬁcally retain TCR (Kraemer et al., Balajee, A.S., Dianova, I., Bohr, V.A., 1999. Oxidative damage-induced PCNA complex

formation is efﬁcient in xeroderma pigmentosum group A but reduced in

1987). Deﬁciencies in repair of transcribed regions cause

Cockayne syndrome group B cells. Nucleic Acids Research 27, 4476–4482.

neurological and developmental disease in human CS patients,

Barnes, D.E., Lindahl, T., 2004. Repair and genetic consequences of endogenous DNA

with no evidence of increased cancer (Nance and Berry, 1992; base damage in mammalian cells. Annual Review of Genetics 445–476.

Cleaver et al., 2009; Weidenheim et al., 2009). Mice with mutations Barrett, S.F., Robbins, J.H., Tarone, R.E., Kraemer, K.H., 1991. Evidence for defective

repair of cyclobutane dimers with normal repair of other photoproducts in a

in TCR, but not humans, show increased skin cancer (van der Horst

transcriptionally active gene transfected into Cockayne syndrome cells. Muta-

et al., 1997; De Gruijl et al., 2001). A partial explanation could be

tion Research 255, 281–291.

based on possible differences between mouse and human in the Beerens, N., Hoeijmakers, J.H., Kanaar, R., Vermeulen, W., Wyman, C., 2005. The CSB

protein actively wraps DNA. Journal of Biological Chemistry 280, 4722–4729.

apoptotic signal from transcription arrest that removes damaged

Bohr, V.A., Smith, C.A., Okumoto, D.S., Hanawalt, P.C., 1985. DNA repair in an active

cells from the tissue (D’Errico et al., 2003, 2005), or in the arrested

gene: removal of pyrimidine dimers from the DHFR gene of CHO cells is much

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autophagy in Csb cells (Scheibye-Knudsen et al., 2012) that more efﬁcient than in the genome overall. Cell 40, 359–369.

Boom, V.v.d., Citterio, E., Hoogstrraten, D., Zotter, A., Egly, J.-M., Cappellen V.A.v.,

may not be mutagenic. In general, however, this dilemma awaits

Hoeijmakers, H.J.H., Hooutsmuller, A.B., Vermeulen, W., 2004. DNA damage

resolution.

stabilizes interaction of CSB with the transcription elongation machinery. The

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0 0

Brooks, P.J., 2007. The case for 8,5 -cyclopurine-2 -deoxynucleosides as endogenous

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Mendes, G.P., Sarasin, A., Menck, C.F., 2003. Effect of cell conﬂuence on ultravi-

mechanisms described above; some may assume greater impor-

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abnormal response of CS to oxidative damage correlates most Citterio, E., Rademakers, S., van der Horst, G.T., van Gool, A.J., Hoeijmakers, J.H.J.,

Vermeulen, W., 1998. Biochemical and biological characterization of wild-type

closely with the major developmental and neurological symptoms

and ATPase-deﬁcient Cockayne syndrome B repair protein. Journal of Biological

of the disease; defective TCR of UV damage seems minimally

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m/m

to reverse the mitochondrial phenotype of Csb cells (Scheibye- Jaruga, P., Ropolo, M., Pedrini, A.M., Orioli, D., Frosina, G., Zambruno, G.,

Dizdaroglu, M., Stefanini, M., Dogliotti, E., 2007. The role of CSA in the response

Knudsen et al., 2012). Activation of autophagy by rapamycin has

to oxidative DNA damage in human cells. Oncogene 26, 4336–4343.

been successful in treatment of a mouse model of TD-43

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cytes. Cancer Research 65, 432–438.

diseases (Wang et al., 2012a).

D’Errico, M., Teson, M., Calcagnile, A., Proietti De Santis, L., Nikaido, O., Botta, E.,

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CS raises hope that some of these approaches will be successful in DNA damage protect human keratinocytes against UVB. Cell Death and Differ-

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improving life and health for CS patients.

da Costa, R.M., Quayle, C., de Fa´tima Jacysyn, J., Amarante-Mendes, G.P., Sarasin, A.,

Menck, C.F., 2008. Resistance to ultraviolet-induced apoptosis in DNA repair

Acknowledgements deﬁcient growth arrested human ﬁbroblasts is not related to recovery from RNA

transcription blockage. Mutation Research 640, 1–7.

de Feraudy, S., Limoli, C.L., Giedzinski, E., Karentz, D., Marti, T.M., Feeney, L., Cleaver,

This work was prepared with the support of the University of J.E., 2007. Pol h is required for DNA replication during nucleotide deprivation by

California E.A.Dickson Emeritus professorship and the Cancer hydroxyurea. Oncogene 26, 5713–5721.

De Gruijl, F.R., Van Kranen, H.J., Mullenders, L.H., 2001. UV-induced DNA damage,

Research Coordinating Committee and the early support from the

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Luke O’Brien Foundation. chemistry and Photobiology B 63, 19–27.

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